106 results on '"Junichi Kawakami"'
Search Results
2. Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients
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Shunta Akutsu, Yasuaki Mino, Takafumi Naito, Kohei Hoshikawa, Masao Saotome, Yuichiro Maekawa, and Junichi Kawakami
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Heart Failure ,Pharmacology ,Genotype ,Tolvaptan ,Amiodarone ,Cytochrome P-450 CYP3A ,Humans ,Pharmacology (medical) ,General Medicine ,Immunosuppressive Agents - Abstract
The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients.Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism.The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5.This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.
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- 2022
3. Impacts of cachexia progression in addition to serum IgG and blood lymphocytes on serum nivolumab in advanced cancer patients
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Atsushi Otsuka, Junichi Kawakami, Masato Karayama, Kazuki Abe, Masato Maekawa, Kaito Shibata, Takafumi Naito, Hideaki Miyake, and Takafumi Suda
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Pharmacology ,medicine.medical_specialty ,biology ,business.industry ,Serum albumin ,Cancer ,General Medicine ,medicine.disease ,Gastroenterology ,Blood proteins ,Immunoglobulin G ,Cachexia ,Internal medicine ,medicine ,biology.protein ,Pharmacology (medical) ,Nivolumab ,Adverse effect ,Lung cancer ,business - Abstract
Serum nivolumab concentrations exhibit a large variation in cancer patients. Cancer cachexia inducing systemic inflammation promotes the elimination of endogenous proteins, while its association with serum nivolumab remains unclear. The present study aimed to evaluate the impacts of cachexia progression in addition to blood components on serum nivolumab in cancer patients. Thirty-eight non-small-cell lung cancer or renal cell cancer patients receiving biweekly intravenous nivolumab were enrolled. Blood samples were collected just before dosing at the 7th administration of nivolumab or later. Serum nivolumab together with serum proteins, inflammatory markers, and peripheral blood leukocytes were determined. Cancer cachexia was classified using the Glasgow Prognostic Score (GPS). Immune-related adverse events (irAEs) were monitored during the study period. Cancer patients had a large variation in serum nivolumab concentrations (interquartile range, 12–21 µg/mL per mg/kg). The serum nivolumab concentration was positively correlated with serum albumin, while negatively associated with serum globulin and immunoglobulin G (IgG). A negative correlation was observed between serum nivolumab and blood lymphocytes. Regarding cachexia progression, the patients with GPS 2 had a higher serum interleukin-6 concentration and a lower serum nivolumab concentration than those with GPS 0 or 1. The GPS, serum IgG, and blood lymphocytes were identified as independent variables for serum nivolumab. The incidence of irAEs was not associated with the nivolumab dose or serum nivolumab. Cachexia progression had a negative impact on serum nivolumab in cancer patients. The interindividual variation in serum nivolumab was characterized by cachexia progression in addition to blood components.
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- 2021
4. Correlations between serum cetuximab and EGFR-related markers, and skin disorders in head and neck cancer patients
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Kaito Shibata, Junichi Kawakami, Satoshi Hirakawa, Hiroyuki Mineta, Seiji Hosokawa, Koji Suzuki, and Takafumi Naito
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0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Toxicology ,Gastroenterology ,Skin Diseases ,Hypomagnesemia ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,cetuximab ,medicine ,Humans ,Pharmacology (medical) ,Magnesium ,Epidermal growth factor receptor ,Prospective Studies ,Adverse effect ,neoplasms ,Aged ,Pharmacology ,Cetuximab ,biology ,integumentary system ,business.industry ,interleukin-6 ,Head and neck cancer ,Cancer ,Middle Aged ,medicine.disease ,Rash ,skin disorder ,digestive system diseases ,ErbB Receptors ,030104 developmental biology ,Oncology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,biology.protein ,Population study ,Female ,head and neck cancer ,medicine.symptom ,business ,epidermal growth factor receptor ,pharmacokinetics ,medicine.drug - Abstract
Purpose: Cetuximab inhibits epidermal growth factor receptor (EGFR) signaling in cancer and skin cells, thereby inducing anti-cancer effects and skin disorders. The present study aimed to evaluate the relationships between serum cetuximab and EGFR-related markers, and adverse effects in head and neck cancer patients.Methods: Thirty-four head and neck cancer patients receiving weekly intravenous cetuximab were enrolled. Serum cetuximab levels were determined just before dosing. Blood samples for determination of serum EGFR-related markers including soluble epidermal growth factor receptor (sEGFR) and interleukin-6 (IL-6) were obtained. The severities of skin disorders, their medications, and hypomagnesemia treatment were also assessed.Results: Serum levels of cetuximab and sEGFR were negatively and positively correlated with that of IL-6, respectively. The serum cetuximab level was 2-fold higher in the patients with a grade 2–3 skin rash than with a grade 0–1 rash. The serum cetuximab cut-off value related to severe skin rash was 71 μg/mL (sensitivity, 59%; and specificity, 94%). The use of a strong topical corticosteroid for skin rash was also associated with a higher serum cetuximab level. Serum levels of sEGFR and IL-6 had no correlations with the skin disorder severities or their medications. Hypomagnesemia treatment using intravenous magnesium sulfate was not related to serum cetuximab and EGFR-related markers.Conclusions: Head and neck cancer patients with a higher serum IL-6 level tended to have a lower serum cetuximab level. Serum cetuximab had positive correlations to skin rash severity and its medication in the study population.
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- 2021
5. Impact of CYP2D6 and Cachexia on Tramadol Kinetics
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Koji Suzuki, Yasuhide Yamada, Takafumi Naito, Kaito Shibata, Kunihiko Itoh, Junichi Kawakami, and Hironari Tanaka
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Male ,tramadol ,CYP2D6 ,medicine.medical_specialty ,Cachexia ,Metabolite ,metabolite ,Central nervous system ,enantiomers ,Toxicology ,030226 pharmacology & pharmacy ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,In patient ,Aged ,Pharmacology ,business.industry ,Head and neck cancer ,Stereoisomerism ,Cancer Pain ,General Medicine ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Cytochrome P-450 CYP2D6 ,chemistry ,Head and Neck Neoplasms ,Female ,Tramadol ,Enantiomer ,business ,030217 neurology & neurosurgery ,cancer cachexia ,medicine.drug - Abstract
This study aimed to evaluate the influence of CYP2D6 activity and cachexia progression on the enantiomeric alteration of plasma tramadol and its demethylated metabolites in head and neck cancer patients. Fifty-three head and neck cancer patients receiving oral tramadol were enrolled. The plasma concentrations of tramadol, O-desmethyltramadol (ODT), and N-desmethyltramadol (NDT) enantiomers were determined. The CYP2D6 activity score (AS) and degree of cachexia progression were assessed according to genotype and the Glasgow Prognostic Score (GPS), respectively. The enantiomeric ratio of NDT was (+)-form dominant in all patients. CYP2D6 AS had negative correlations with the plasma concentrations of (+)-NDT and (−)-NDT. The plasma concentrations of (+)-tramadol and (+)-ODT were higher in patients with GPS 1 or 2 than in those with GPS 0. Lower metabolic ratios to NDT enantiomers were observed in patients with GPS 1 or 2. In patients with GPS 1 or 2, the plasma (−)-tramadol was associated with the incidence of central nervous system symptoms. In conclusion, CYP2D6 AS partially explained the contribution of CYP2D6 activity to plasma tramadol and its demethylated metabolite enantiomers. Additionally, cachexia progression elevated the plasma (+)-tramadol and (+)-ODT levels through the reduction of N-demethylation of (+)-tramadol.
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- 2020
6. Impact of CYP3A5 genotype on tolvaptan pharmacokinetics and their relationships with endogenous markers of CYP3A activity and serum sodium level in heart failure patients
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Masao Saotome, Junichi Kawakami, Shunta Akutsu, Kohei Hoshikawa, Takafumi Naito, and Yuichiro Maekawa
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Male ,medicine.medical_specialty ,CYP3A5 ,ATP Binding Cassette Transporter, Subfamily B ,Genotype ,CYP3A ,Tolvaptan ,Volume overload ,Endogeny ,Toxicology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,4β-hydroxycholesterol ,Medicine ,Cytochrome P-450 CYP3A ,Humans ,Vitamin D ,Alleles ,Aged ,Pharmacology ,Aged, 80 and over ,Heart Failure ,business.industry ,tolvaptan ,Sodium ,ABCB1 ,General Medicine ,medicine.disease ,Hydroxycholesterols ,Endocrinology ,Cholesterol ,Heart failure ,Female ,business ,pharmacokinetics ,030217 neurology & neurosurgery ,Antidiuretic Hormone Receptor Antagonists ,medicine.drug - Abstract
Tolvaptan efficacy for heart failure has a large interindividual variation. This study aimed to evaluate the influence of CYP3A5 and ABCB1 genotypes on tolvaptan pharmacokinetics and their relationships with plasma markers of CYP3A activity and laboratory test values in heart failure patients. Fifty-eight heart failure patients receiving oral tolvaptan for volume overload were enrolled. Blood samples for determination of pre-dose plasma concentrations of tolvaptan and its metabolites were collected. CYP3A5 and ABCB1 genotypes, plasma 4β-hydroxycholesterol/total cholesterol ratio (4β-OHC/TC) and 25-hydroxyvitamin D (25-OHD), and serum laboratory test values were evaluated. The CYP3A5*3/*3 genotype was associated with a higher plasma concentration of tolvaptan but not with its metabolic ratios. The ABCB1 3435C > T, 2677G > T/A and 1236C > T polymorphisms affected neither tolvaptan pharmacokinetics nor its metabolism. Plasma 4β-OHC/TC and 25-OHD concentration were not correlated with plasma tolvaptan concentration. In a stratified analysis based on CYP3A5 genotype, plasma 4β-OHC/TC had a negative correlation with plasma tolvaptan concentration in the patients with the CYP3A5*1 allele, while the plasma concentration of 25-OHD did not. The CYP3A5*3/*3 genotype was associated with a higher serum sodium level in the patients with volume overload. The plasma concentration of 25-OHD had a positive correlation with the serum total bilirubin level. In conclusion, CYP3A5*3 but not ABCB1 genotypes elevated tolvaptan plasma exposure in heart failure patients. CYP3A5-deficient patients treated with tolvaptan had a higher serum sodium level. The CYP3A5 genotype altered the relationship between plasma tolvaptan and 4β-OHC.
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- 2020
7. Impact of Light Shielding on Photo-Degradation of Dacarbazine during the Preparation Process
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Chikoto Yamamoto, Junichi Kawakami, Shin-Ya Katoh, Takafumi Naito, and Masaki Tashiro
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0301 basic medicine ,Light ,Peripheral intravenous ,Dacarbazine ,Pharmaceutical Science ,03 medical and health sciences ,0302 clinical medicine ,Drug Stability ,medicine ,Photodegradation ,Dissolution ,Light exposure ,Pharmacology ,Photolysis ,Chemistry ,Radiochemistry ,Imidazoles ,Temperature ,General Medicine ,Solutions ,030104 developmental biology ,Compounding ,030220 oncology & carcinogenesis ,Electromagnetic shielding ,Uv detection ,medicine.drug - Abstract
Dacarbazine (DTIC) is converted to the photo-degradation product 4-diazoimidazole-5-carboxamide (Diazo-IC) by light. Diazo-IC production is often responsible for the pain reactions observed during peripheral intravenous infusion of DTIC in clinical settings. Although light shielding during infusion decreases the photo-degradation of DTIC, its usefulness for the preparation of DTIC has not yet been fully clarified. The aim of this study was to investigate the light conditions during the preparation of DTIC solution in the compounding room from the viewpoint of the production amount of Diazo-IC. DTIC solution was prepared in the compounding room. Various light and temperature conditions and dissolving solutions during the preparation were investigated. The amounts of DTIC and Diazo-IC in solutions were determined using an HPLC coupled to UV detection. The photo-degradation of DTIC was estimated by the amount of Diazo-IC. Diazo-IC production in the dissolving solutions increased in a time-dependent manner at 4 and 25°C under light shielding. Light exposure during the dissolving process did not affect the DTIC and Diazo-IC concentrations. Light shielding during dissolution did not alter the Diazo-IC production until 4 h after dilution. In conclusion, short duration light exposure did not affect Diazo-IC production. These findings suggest that light shielding is not needed in the preparation of DTIC in the compounding room from the viewpoint of Diazo-IC production.
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- 2019
8. Impact of flavin-containing monooxygenase 3 and CYP2C19 genotypes on plasma disposition and adverse effects of voriconazole administered orally in immunocompromised patients
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Junichi Kawakami, Takafumi Naito, Takahiro Yamada, and Yasuaki Mino
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Male ,0301 basic medicine ,Microbiology (medical) ,Antifungal Agents ,Genotype ,030106 microbiology ,Administration, Oral ,Flavin-containing monooxygenase ,CYP2C19 ,Pharmacology ,Immunocompromised Host ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Liver Function Tests ,Pharmacokinetics ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Adverse effect ,Aged ,Voriconazole ,biology ,business.industry ,Incidence ,Cytochrome P450 ,Middle Aged ,Monooxygenase ,Cytochrome P-450 CYP2C19 ,Infectious Diseases ,Mycoses ,Oxygenases ,biology.protein ,Female ,Chemical and Drug Induced Liver Injury ,business ,medicine.drug - Abstract
Flavin-containing monooxygenase (FMO) 3 together with cytochrome P450 (CYP) 2C19 play a significant role in voriconazole N-oxidation. This study aimed to evaluate the influence of FMO3 and CYP2C19 genotypes on the plasma disposition and adverse effects of voriconazole in immunocompromised patients. Sixty-five Japanese immunocompromised patients receiving oral voriconazole were enrolled. Predose plasma concentrations of voriconazole and N-oxide were determined at day 5 or later. The adverse effects of voriconazole and the FMO3 and CYP2C19 genotypes were investigated. The patients with FMO3 E158K/E308G had a lower plasma concentration of voriconazole. The metabolic ratio to N-oxide was significantly higher in the FMO3 E158K/E308G group than in the wild group. In contrast, FMO3 V257M was not associated with the plasma concentration of voriconazole. No significant difference was observed in the saturation index, defined as a correlation coefficient of the regression line between the absolute plasma concentration of voriconazole and the inverse value of the metabolic ratio to N-oxide, between the FMO3 genotypes. CYP2C19 phenotype did not affect the plasma concentration and metabolic ratio of voriconazole. The saturation index of voriconazole rose in the order of CYP2C19 extensive, intermediate, and then poor metabolizer groups. However, the FMO3 and CYP2C19 genotypes and their associated voriconazole pharmacokinetics did not have an effect on the incidence of adverse effects. In conclusion, FMO3 E158K/E308G decreased the plasma concentration of voriconazole through its higher metabolic activity. The FMO3 genotype altered the plasma exposure of voriconazole, while the CYP2C19 phenotype affected the metabolic capacity in immunocompromised patients.
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- 2019
9. Impact of Cachexia and Opioid Analgesic Cotreatment on Pregabalin Pharmacokinetics and Central Nervous System Symptoms in Cancer Patients
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Tatsuya Yagi, Nozomi Yoshikawa, Junichi Kawakami, and Takafumi Naito
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Cachexia ,Central nervous system ,Pregabalin ,Nervous System ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Central Nervous System Diseases ,Neoplasms ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Aged ,Pain Measurement ,Pharmacology ,business.industry ,Incidence (epidemiology) ,Cancer ,Middle Aged ,medicine.disease ,Analgesics, Opioid ,C-Reactive Protein ,medicine.anatomical_structure ,Opioid ,Female ,Opioid analgesics ,business ,Glomerular Filtration Rate ,medicine.drug - Abstract
Patients with cancer receiving pregabalin potentially have a high incidence of central nervous system (CNS) symptoms. The purpose of this study was to explore clinical factors influencing the incidence of CNS symptoms, including plasma pregabalin exposure, cancer cachexia, and opioid analgesic cotreatment.Sixty-eight patients with cancer receiving twice-daily pregabalin were enrolled. Plasma concentrations of pregabalin, clinical laboratory data, opioid analgesic cotreatment, and the Glasgow Prognostic Score, which is an inflammation-based cachexia score, were considered as clinical factors. The incidence of CNS symptoms was collected from the patients' medical records. The predose plasma concentrations of pregabalin at steady state were determined by ultra-high-performance liquid chromatography.The steady-state trough plasma pregabalin concentrations showed a large variability with an interquartile range of 0.43-1.2 mg/L per mg/kg and were negatively correlated with an estimated glomerular filtration rate (eGFR). C-reactive protein (standardized partial regression coefficient, β = 0.31) and opioid analgesic cotreatment (β = 0.24) were also identified in addition to eGFR (β = -0.60) in the multiple regression analysis. The incidence of CNS symptoms was significantly increased with opioid analgesic cotreatment and a higher Glasgow Prognostic Score but not with the absolute value of plasma pregabalin concentrations, eGFR, or other clinical laboratory data.In patients with cancer, steady-state trough plasma pregabalin concentrations were altered with renal function, systemic inflammation, and opioid analgesic cotreatment. However, a higher incidence of CNS symptoms observed in patients with cancer on pregabalin was more related to cachexia and opioid analgesic cotreatment than to altered pregabalin concentrations.
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- 2019
10. Maternal Plasma and Cord Blood Concentration Profiles of Duloxetine During the Peripartum Period and Their Associations With the Modified Finnegan Score
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Junichi Kawakami, Koji Suzuki, Takafumi Naito, Yuko Kurosawa, Hiroaki Itoh, and Reina Taguchi
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Pharmacology ,business.industry ,Duloxetine Hydrochloride ,Fetal Blood ,chemistry.chemical_compound ,Plasma ,chemistry ,Risk Factors ,Cord blood ,Anesthesia ,Peripartum Period ,Medicine ,Duloxetine ,Humans ,Pharmacology (medical) ,business - Published
- 2021
11. Prediction of the Area under the Curve Using Limited-Point Blood Sampling in a Cocktail Study to Assess Multiple CYP Activities
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Junichi Kawakami, Naoki Inui, Shimako Tanaka, Hiroshi Watanabe, Keiichi Odagiri, Naoki Katayama, Shinya Uchida, Chiaki Kamiya, Motoyasu Miura, Noriyuki Namiki, and Akio Hakamata
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0301 basic medicine ,Adult ,Male ,Midazolam ,Pharmaceutical Science ,Administration, Oral ,Pharmacology ,Dextromethorphan ,Models, Biological ,Losartan ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Cytochrome P-450 Enzyme System ,In vivo ,Caffeine ,Linear regression ,Medicine ,Humans ,Cimetidine ,Omeprazole ,business.industry ,Area under the curve ,General Medicine ,030104 developmental biology ,030220 oncology & carcinogenesis ,Area Under Curve ,business ,medicine.drug ,Blood sampling - Abstract
A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were
- Published
- 2021
12. Simple Liquid Chromatography-Tandem Mass Spectrometry Method for Quantitation of Total and Free Aprepitant and its Active N-Dealkylated Metabolites in Human Plasma
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Junichi Kawakami, Kaito Shibata, Takafumi Naito, and Yusuke Suzuki
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Spectrometry, Mass, Electrospray Ionization ,Analyte ,medicine.drug_class ,Electrospray ionization ,Ultrafiltration ,Mass spectrometry ,030226 pharmacology & pharmacy ,Plasma ,03 medical and health sciences ,0302 clinical medicine ,Tandem Mass Spectrometry ,Liquid chromatography–mass spectrometry ,medicine ,Humans ,Antiemetic ,Pharmacology (medical) ,Aprepitant ,Pharmacology ,Chromatography ,Chemistry ,Reproducibility of Results ,Free fraction ,Calibration ,Chromatography, Liquid ,medicine.drug - Abstract
BACKGROUND Aprepitant, an antiemetic selective neurokinin-1 receptor antagonist, is primarily metabolized to the active N-dealkylated form (ND-AP) and then converted to its carbonyl form (ND-CAP) in humans. This study developed a simple liquid chromatography-tandem mass spectrometry method using electrospray ionization for the quantitation of plasma total and free aprepitant and its N-dealkylated metabolites and used them to analyze patient plasma. METHODS Free aprepitant and ND-AP in plasma were fractionated using centrifugal ultrafiltration. The analytes in plasma or their ultrafiltered specimens treated with triethylamine/acetonitrile were isocratically separated using a 3-μm octadecylsilyl column with a total run time of 10 minutes and scanned using positive ion electrospray ionization. RESULTS The calibration curves of total aprepitant, ND-AP, and ND-CAP were prepared at concentration ranges of 50-2500, 20-1000, and 5-250 ng/mL, respectively, whereas that of free aprepitant and ND-AP were at a concentration range of 2-150 ng/mL. The intraassay and interassay accuracy and imprecision values were 93.5%-107.7% and 94.6%-103.3%, and 2.1%-7.5% and 1.0%-8.9%, respectively. Aprepitant and its metabolites did not exhibit any matrix effects or instabilities in the plasma specimens. In cancer patients receiving oral aprepitant, the plasma concentration ranges of total aprepitant, ND-AP, and ND-CAP, and free aprepitant and ND-AP were 137-2170, 104-928, 22.4-97.6, 8.11-60.0, and 3.53-56.0 ng/mL, respectively. The median plasma free fraction proportion of aprepitant and ND-AP was 4.14% and 4.90%, respectively. CONCLUSIONS The present developed method showed an acceptable analytical performance and can be used to evaluate total and free aprepitant and its N-dealkylated metabolites in patient plasma.
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- 2020
13. Associations between plasma hydroxylated metabolite of itraconazole and serum creatinine in patients with a hematopoietic or immune-related disorder
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Junichi Kawakami, Yumi Imoto, Yukari Miyadera, Takaaki Ono, and Takafumi Naito
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Male ,medicine.medical_specialty ,Antifungal Agents ,Itraconazole ,Metabolite ,metabolite ,Renal function ,Administration, Oral ,Hydroxylation ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Cystatin C ,Aged ,Pharmacology ,Creatinine ,biology ,business.industry ,renal function ,General Medicine ,Middle Aged ,Hematologic Diseases ,Endocrinology ,chemistry ,Immune System Diseases ,Concomitant ,biology.protein ,Female ,business ,pharmacokinetics ,Glucocorticoid ,medicine.drug ,Glomerular Filtration Rate - Abstract
Purpose: Serum markers of renal function have not been characterized in patients treated with itraconazole (ITZ). This study aimed to evaluate the associations between plasma ITZ and its hydroxylated metabolite (OH-ITZ) concentrations and serum markers of renal function in hematopoietic or immune-related disorder patients.Methods: This study enrolled 40 hematopoietic or immune-related disorder patients receiving oral ITZ solution. Plasma concentrations of ITZ and OH-ITZ at 12 hours after dosing were determined at steady state. Their relationships with serum levels of creatinine and cystatin C, and their estimated glomerular filtration rate (eGFR) were evaluated.Results: The free plasma concentration of ITZ had no correlation with serum creatinine and serum creatinine-based estimated glomerular filtration rate (eGFR-cre). The free plasma concentration of OH-ITZ was positively and negatively correlated with serum creatinine and eGFR-cre, respectively. The free plasma concentrations of ITZ and OH-ITZ had no association with serum cystatin C and serum cystatin C-based eGFR. Serum creatinine was higher by 16% after than before starting ITZ treatment, while eGFR-cre was lower by 9.3%. The serum creatinine ratio after/before ITZ treatment was positively correlated with the free plasma concentration of OH-ITZ. The patients co-treated with trimethoprim-sulfamethoxazole had higher serum creatinine. Concomitant glucocorticoid administration did not significantly alter serum cystatin C.Conclusions: Hematopoietic or immune-related disorder patients treated with oral ITZ had a higher level of serum creatinine. Although serum creatinine potentially increases in conjunction with the free plasma concentration of OH-ITZ, concomitant ITZ administration has a slight impact on the eGFR-cre level in clinical settings.
- Published
- 2020
14. Impact of CYP genotype and inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients
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Hikaru Sato, Hironari Tanaka, Junichi Kawakami, Takanori Hiraide, Yasuhide Yamada, and Takafumi Naito
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Male ,CYP2D6 ,Time Factors ,Genotype ,CYP2B6 ,Metabolite ,Administration, Oral ,Pharmacology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Asian People ,Cytochrome P-450 Enzyme System ,Pharmacokinetics ,Neoplasms ,Humans ,Medicine ,Pharmacology (medical) ,CYP3A5 ,Tramadol ,Aged ,Interleukin-6 ,business.industry ,Cancer Pain ,General Medicine ,Middle Aged ,Analgesics, Opioid ,C-Reactive Protein ,Cytochrome P-450 CYP2D6 ,chemistry ,Tolerability ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Clinical responses to oral tramadol show a large variation in cancer patients. This study aimed to evaluate the impacts of cytochrome P450 (CYP) genotype and serum inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients. The predose plasma concentrations of tramadol and its demethylated metabolites were determined at day 4 or later in 70 Japanese cancer patients treated with oral tramadol. The CYP genotypes, serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels, and the duration of tramadol treatment were evaluated. The CYP2D6 genotype did not affect the plasma tramadol concentration. The plasma concentration of O-desmethyltramadol and its ratio to tramadol were lower in the CYP2D6 intermediate and poor metabolizer (IM + PM) group than in the normal metabolizer (NM) group (P = 0.002 and P = 0.023). The plasma concentration of N-desmethyltramadol and its ratio to tramadol were higher in the CYP2D6 IM + PM group than in the NM group (P = 0.001 and P = 0.001). The CYP2B6*6 and CYP3A5*3 alleles had no effect on the plasma concentrations of tramadol and its demethylated metabolites. The serum IL-6 and CRP levels were inversely correlated with the plasma concentration ratios of N-desmethyltramadol to tramadol and of N,O-didesmethyltramadol to O-desmethyltramadol. The serum IL-6 level was associated with the treatment duration of oral tramadol. The CYP2D6 genotype but not the CYP2B6 and CYP3A5 genotypes affected the plasma concentrations of O- and N-desmethyltramadol through alteration of the tramadol metabolic pathway. The serum IL-6 level was associated with N-demethylation activity and tramadol tolerability.
- Published
- 2018
15. A Validated Fluorometric Method for the Rapid Determination of Pregabalin in Human Plasma Applied to Patients With Pain
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Tatsuya Yagi, Junichi Kawakami, Nozomi Yoshikawa, and Takafumi Naito
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Accuracy and precision ,Cyclohexanecarboxylic Acids ,Gabapentin ,Calibration curve ,Pregabalin ,Pain ,030226 pharmacology & pharmacy ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,Limit of Detection ,medicine ,Humans ,Protein precipitation ,Fluorometry ,Pharmacology (medical) ,Amines ,Chromatography, High Pressure Liquid ,gamma-Aminobutyric Acid ,Pharmacology ,Detection limit ,Analgesics ,Chromatography ,medicine.diagnostic_test ,Chemistry ,010401 analytical chemistry ,Reference Standards ,Data Accuracy ,0104 chemical sciences ,Therapeutic drug monitoring ,Human plasma ,Anesthesia ,medicine.drug - Abstract
BACKGROUND Pregabalin has been used for the treatment of pain. A clinically accepted method applied to patients with pain has not been published for the determination of pregabalin in human plasma. This study developed a fluorometric ultrahigh-performance liquid chromatography (UHPLC) method to measure pregabalin concentration in patients with pain. METHODS After plasma pretreatment involving protein precipitation, pregabalin and gabapentin as an internal standard were derivatized with 4-fluoro-7-nitrobenzofurazan (NBD-F) under the following reaction conditions: 1 minute, pH 10, and 60°C. The UHPLC separation was performed using a 2.3-μm particle size octadecylsilyl column. The fluorescence detector was set at excitation and emission wavelengths of 470 and 530 nm, respectively. The predose blood samples were collected from 40 patients with pain who have been treated with 75 mg of pregabalin twice daily. RESULTS The chromatographic run time was 1.25 minutes. No interfering peaks were observed in the blank plasma at the retention times of NBD derivatives. The calibration curve of pregabalin was linear at a range of 0.05-10 mcg/mL (r > 0.999). The lower limit of quantification was 0.05 mcg/mL. The intra-assay accuracy and precision were 98.3%-99.8% and within 4.3%, respectively. The inter-assay accuracy and precision were 103.2%-107.1% and within 4.1%, respectively. The predose plasma concentration of pregabalin in patients with pain ranged from 0.14 to 8.5 mcg/mL. CONCLUSIONS This study provides a validated fluorometric UHPLC method with fast analytical performance for the determination of pregabalin in human plasma. The present method could be applied to patients with pain and be used for the clinical research or therapeutic drug monitoring of pregabalin.
- Published
- 2016
16. The Prediction of the Area under the Curve and Clearance of Midazolam from Single-Point Plasma Concentration and Urinary Excretion in Healthy Volunteers
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Junichi Kawakami, Shinya Uchida, Hiroshi Watanabe, Noriyuki Namiki, Naoki Inui, Motoyasu Miura, and Shimako Tanaka
- Subjects
Time Factors ,genetic structures ,Metabolic Clearance Rate ,Midazolam ,Pharmaceutical Science ,Administration, Oral ,Urine ,Urinary excretion ,Pharmacokinetics ,Oral administration ,Predictive Value of Tests ,mental disorders ,Medicine ,Cytochrome P-450 CYP3A ,Humans ,heterocyclic compounds ,Retrospective Studies ,Pharmacology ,Cross-Over Studies ,CYP3A4 ,Dose-Response Relationship, Drug ,business.industry ,Area under the curve ,General Medicine ,Healthy Volunteers ,Anesthesia ,Area Under Curve ,Injections, Intravenous ,business ,psychological phenomena and processes ,Blood sampling ,medicine.drug - Abstract
There are large inter- and intra-individual variations in CYP3A4 activity. Midazolam, which is predominantly metabolized to 1'-hydroxymidazolam and 4-hydroxymidazolam by CYP3A4, is considered an effective probe for CYP3A4. To determine the area under the curve (AUC) of midazolam or midazolam clearance for CYP3A4 activity, multiple plasma samples of midazolam are required. This study aimed to evaluate whether measurement of a single plasma concentration or urinary excretion of midazolam could be used to predict the AUC of midazolam in healthy volunteers. We conducted a retrospective analysis of two pharmacokinetic studies. Nineteen volunteers received intravenous (5, 15, and 30 µg/kg) and oral (15, 50, and 100 µg/kg) administration of midazolam on sequential days. The midazolam concentration in plasma and urine was determined by LC-MS/MS. Plasma midazolam concentrations showed a good correlation with the AUC at all blood sampling points after the administrations. The coefficient of determination was highest at 1-2 and 2-4 h after intravenous (>0.96) and oral administration (>0.94), respectively, among all the sampling times. The errors for bias and accuracy of prediction were the lowest at 1.5 and 4 h after intravenous and oral administration, respectively. In case of urinary excretion, a significant positive correlation between midazolam and the AUC was observed only after oral administration. Thus, the AUC of midazolam can be evaluated by blood sampling at 1.5 h after intravenous administration and at 4 h after oral administration.
- Published
- 2019
17. Evaluating the impact of regulatory action on denosumab-induced hypocalcaemia in Japan
- Author
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Katsuhito Hori, Kimie Sai, Yoko Kataoka, Takanori Yamashita, Yoshiro Saito, Tatsuo Hiramatsu, Naoki Nakashima, Michio Kimura, Katsunori Segawa, Takuya Imatoh, Junichi Kawakami, Kazuhiko Ohe, Mayu Takeyama, and Hideto Yokoi
- Subjects
Male ,medicine.medical_specialty ,Databases, Factual ,Medical information ,030226 pharmacology & pharmacy ,Zoledronic Acid ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Risk Factors ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Pharmacology (medical) ,Hypocalcaemia ,030212 general & internal medicine ,Vitamin D ,Calcium tests ,Aged ,Pharmacology ,Bone Density Conservation Agents ,Hypocalcemia ,business.industry ,Significant difference ,medicine.disease ,Denosumab ,Zoledronic acid ,Serum calcium test ,Calcium ,Female ,business ,medicine.drug - Abstract
What is known and objective Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). Methods We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. Results and discussion The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. What is new and conclusion There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.
- Published
- 2019
18. Relationships between oxycodone pharmacokinetics, central symptoms, and serum interleukin-6 in cachectic cancer patients
- Author
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Junichi Kawakami, Takuya Ishida, Hikaru Sato, and Takafumi Naito
- Subjects
Male ,Cachexia ,Interleukin-1beta ,Disorders of Excessive Somnolence ,Pharmacology ,030226 pharmacology & pharmacy ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Neoplasms ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Pharmacology (medical) ,Interleukin 6 ,Aged ,biology ,CYP3A4 ,Depression ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Delirium ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Analgesics, Opioid ,Cytochrome p450 enzyme ,Delayed-Action Preparations ,030220 oncology & carcinogenesis ,biology.protein ,Female ,business ,Oxycodone ,medicine.drug - Abstract
Elevated serum proinflammatory cytokines are associated with the reduction of cytochrome P450 enzyme (CYP) activity. This study aimed to evaluate the oxycodone pharmacokinetics, central symptoms, and serum proinflammatory cytokines based on cachexia stage in cancer patients.Forty-seven cancer patients receiving extended-release oxycodone were enrolled. Predose plasma concentrations of oxycodone and its metabolites were normalized with the daily dose and body weight. The central symptoms and serum level of proinflammatory cytokines were investigated at each cachexia stage.The plasma concentrations of oxycodone in patients with cachexia and refractory cachexia were significantly higher than that in patients with precachexia. The metabolic ratio to noroxycodone in patients with cachexia was significantly lower than that in patients with precachexia. The patients with a higher cachexia stage had a higher serum level of interleukin-6 (IL-6), but not tumor necrosis factor-α and interleukin-1β. The serum IL-6 level was correlated with the plasma concentration of oxycodone and inversely with the metabolic ratio to noroxycodone. The incidence of somnolence was not associated with the plasma oxycodone concentration. In contrast, the cachexia stage and its associated serum IL-6 level were correlated with the incidence of somnolence.Cancer cachexia raised the plasma exposure of oxycodone through the reduction of CYP3A metabolic pathway. The reduction of CYP3A in cachectic cancer patients was associated with an elevation of serum IL-6. Although cachectic cancer patients with higher serum IL-6 levels had the symptom of somnolence, the alterations in oxycodone pharmacokinetics were not related to the incidence of symptom.
- Published
- 2016
19. Mycophenolic acid exposure and complement fraction C3 influence inosine 5′-monophosphate dehydrogenase activity in systemic lupus erythematosus
- Author
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Junichi Kawakami, Noriyoshi Ogawa, Takafumi Naito, Kumiko Shimoyama, and Yasuaki Mino
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Adult ,Male ,Clinical Biochemistry ,Dehydrogenase ,030204 cardiovascular system & hematology ,Pharmacology ,Mycophenolate ,Xanthine ,030226 pharmacology & pharmacy ,Drug Administration Schedule ,Mycophenolic acid ,03 medical and health sciences ,Glucuronides ,IMP Dehydrogenase ,0302 clinical medicine ,Pharmacokinetics ,Humans ,Lupus Erythematosus, Systemic ,Medicine ,Inosine-5′-monophosphate dehydrogenase ,Inosine ,chemistry.chemical_classification ,biology ,business.industry ,Body Weight ,Remission Induction ,Complement C3 ,General Medicine ,Middle Aged ,Mycophenolic Acid ,Ribonucleotides ,Cross-Sectional Studies ,Enzyme ,chemistry ,Multivariate Analysis ,biology.protein ,Female ,business ,Glucuronide ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Mycophenolate mofetil has recently been reported to be effective against systemic lupus erythematosus. The influence of the pharmacokinetics of mycophenolic acid, the active form of mycophenolate mofetil and the major inactive mycophenolic acid phenolic glucuronide on the activity of the target enzyme inosine 5′-monophosphate dehydrogenase, is expected to be revealed. The aim of this study was to identify the factors associated with inosine 5′-monophosphate dehydrogenase activity in systemic lupus erythematosus patients. Methods Fifty systemic lupus erythematosus patients in remission maintenance phase (29 received mycophenolate mofetil [MMF+] and 21 did not [MMF−]) were enrolled. Median and interquartile range of dose of mycophenolate mofetil were 1500 and 1000–1500 mg/day, respectively. Stepwise multiple linear regression analysis was performed to assess the dependence between inosine 5′-monophosphate dehydrogenase activity and 25 predictor values including predose plasma concentrations of free mycophenolic acid and mycophenolic acid phenolic glucuronide. Results Median and interquartile range of predose total plasma concentrations of mycophenolic acid and mycophenolic acid phenolic glucuronide were 2.73 and 1.43–5.73 and 25.5 and 13.1–54.7 µg/mL, respectively. Predose inosine 5′-monophosphate dehydrogenase activity was significantly higher in MMF+ than MMF− patients (median 38.3 and 20.6 nmoL xanthosine 5′-monophosphate/g haemoglobin/h, P2 = 0.52, P Conclusions Predose inosine 5′-monophosphate dehydrogenase activity was higher in systemic lupus erythematosus patients receiving mycophenolate mofetil therapy. Inosine 5′-monophosphate dehydrogenase activity may be determined by mycophenolic acid exposure and complement fraction C3 in systemic lupus erythematosus patients.
- Published
- 2016
20. CYP3A activity based on plasma 4β-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine
- Author
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Hiroaki Itoh, Takuya Ishida, Junichi Kawakami, Shuhei Deguchi, Naohiro Kanayama, Naoko Kubono, Masahisa Sugihara, and Takafumi Naito
- Subjects
Adult ,medicine.medical_specialty ,CYP3A ,Pharmaceutical Science ,Substrate Specificity ,chemistry.chemical_compound ,Pharmacokinetics ,Pregnancy ,Internal medicine ,polycyclic compounds ,Cytochrome P-450 CYP3A ,Humans ,Medicine ,Pharmacology (medical) ,Amlodipine ,Antihypertensive Agents ,Biotransformation ,Pharmacology ,CYP3A4 ,business.industry ,Cholesterol ,Postpartum Period ,Hypertension, Pregnancy-Induced ,Disposition ,Calcium Channel Blockers ,medicine.disease ,Hydroxycholesterols ,Up-Regulation ,Endocrinology ,chemistry ,Female ,lipids (amino acids, peptides, and proteins) ,business ,Biomarkers ,Postpartum period ,medicine.drug - Abstract
This study aimed to evaluate plasma 4β-hydroxycholesterol as an endogenous marker of CYP3A4/5 activity in early postpartum women and its impact on the plasma disposition of amlodipine. Twenty-seven early postpartum women treated with amlodipine for pregnancy-induced hypertension were enrolled. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum and in non-perinatal women were evaluated. The predose plasma concentration of amlodipine was determined at steady state. The medians of the plasma 4β-hydroxycholesterol concentration at day 0-3 and 8-21 after delivery were 146 and 161 ng/mL, respectively. No significant difference was observed in the plasma concentration of 4β-hydroxycholesterol between the postpartum periods. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum women were significantly higher than those in non-perinatal women. A large individual variability was observed in the dose-normalized plasma concentration of amlodipine in early postpartum women. A weak negative correlation was observed between the dose-normalized plasma concentration of amlodipine and the plasma concentration of 4β-hydroxycholesterol. In conclusion, early postpartum women possessed higher CYP3A activity based on plasma 4β-hydroxycholesterol and had a large pharmacokinetic variability in amlodipine. CYP3A activity during the early postpartum period had an effect on the plasma disposition of amlodipine.
- Published
- 2015
21. From a Viewpoint of Clinical Settings: Pharmacoepidemiology as Reverse Translational Research (rTR)
- Author
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Junichi Kawakami
- Subjects
Drug-Related Side Effects and Adverse Reactions ,Pharmaceutical Science ,Translational research ,030226 pharmacology & pharmacy ,law.invention ,Translational Research, Biomedical ,Health Information Systems ,03 medical and health sciences ,0302 clinical medicine ,law ,Product Surveillance, Postmarketing ,Humans ,Medicine ,030212 general & internal medicine ,Adverse effect ,Risk management ,Pharmacology ,Estimation ,Risk Management ,Clinical pharmacology ,business.industry ,Pharmacoepidemiology ,Medical record ,medicine.disease ,Databases as Topic ,Scale (social sciences) ,Medical emergency ,business - Abstract
Clinical pharmacology and pharmacoepidemiology research may converge in practise. Pharmacoepidemiology is the study of pharmacotherapy and risk management in patient groups. For many drugs, adverse reaction(s) that were not seen and/or clarified during research and development stages have been reported in the real world. Pharmacoepidemiology can detect and verify adverse drug reactions as reverse translational research. Recently, development and effective use of medical information databases (MID) have been conducted in Japan and elsewhere for the purpose of post-marketing safety of drugs. The Ministry of Health, Labour and Welfare, Japan has been promoting the development of 10-million scale database in 10 hospitals and hospital groups as "the infrastructure project of medical information database (MID-NET)". This project enables estimation of the frequency of adverse reactions, the distinction between drug-induced reactions and basal health-condition changes, and usefulness verification of administrative measures of drug safety. However, because the database information is different from detailed medical records, construction of methodologies for the detection and evaluation of adverse reactions is required. We have been performing database research using medical information system in some hospitals to establish and demonstrate useful methods for post-marketing safety. In this symposium, we aim to discuss the possibility of reverse translational research from clinical settings and provide an introduction to our research.
- Published
- 2017
22. Simple LC-MS/MS Methods Using Core-Shell Octadecylsilyl Microparticulate for the Quantitation of Total and Free Daptomycin in Human Plasma
- Author
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Takahiro Yamada, Junichi Kawakami, Yukari Miyadera, and Takafumi Naito
- Subjects
0301 basic medicine ,Electrospray ionization ,030106 microbiology ,Ultrafiltration ,Mass spectrometry ,Tandem mass spectrometry ,01 natural sciences ,Sensitivity and Specificity ,03 medical and health sciences ,Pharmacokinetics ,Daptomycin ,Drug Stability ,Limit of Detection ,Tandem Mass Spectrometry ,polycyclic compounds ,medicine ,Humans ,Pharmacology (medical) ,Pharmacology ,Chromatography ,Chemistry ,Elution ,010401 analytical chemistry ,Extraction (chemistry) ,bacterial infections and mycoses ,Silicon Dioxide ,0104 chemical sciences ,Calibration ,lipids (amino acids, peptides, and proteins) ,medicine.drug ,Chromatography, Liquid - Abstract
BACKGROUND Daptomycin, a cyclic lipopeptide antibiotic, displays high plasma protein binding. This study developed the simple method of liquid chromatographic separation using a core-shell octadecylsilyl microparticulate coupled to tandem mass spectrometry for the quantitation of total and free daptomycin in human plasma. METHODS Free daptomycin in plasma was obtained by centrifugal ultrafiltration. Deproteinized plasma specimens were directly separated using a core-shell octadecylsilyl microparticulate with isocratic elution. The mass spectrometer was run in positive-ion electrospray ionization mode. This method was applied to the quantitation of plasma samples in patients treated with intravenous daptomycin. RESULTS Daptomycin and diazepam as an internal standard were eluted with a total run time of 10 minutes. The calibration curves of total and free daptomycin in human plasma were linear over the concentration ranges of 1-100 and 0.1-10 mcg/mL, respectively. The lower limits of quantitation of the total and free daptomycin in human plasma were 1.0 and 0.1 mcg/mL, respectively. Their extraction recovery rates in nonfiltrated and ultrafiltrated plasma samples were 106.1% and 98.2%, respectively. Total and free daptomycin did not exhibit any matrix effects in human plasma. The intraday and interday accuracies and imprecisions of total daptomycin were 88.7%-106.0% and 98.7%-105.9%, and within 4.1% and 10.4%, whereas those of free daptomycin were 86.8%-101.6% and 103.0%-107.8%, and within 14.6% and 14.6%, respectively. The plasma concentration ranges of total and free daptomycin in 15 infected patients were 3.01-34.1 and 0.39-3.64 mcg/mL, respectively. The plasma protein binding rate of daptomycin ranged from 80.8% to 94.9%. CONCLUSIONS The present simple method with an acceptable analytical performance can be helpful for monitoring the pharmacokinetics of daptomycin in infected patients observed in clinical settings.
- Published
- 2018
23. Identification of risk factors and development of detection algorithm for denosumab-induced hypocalcaemia
- Author
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Takuya Imatoh, Masato Karayama, Katsunori Segawa, Michio Kimura, Yoshiro Saito, Kimie Sai, Junichi Kawakami, Katsuhito Hori, Kazuki Furuhashi, and Mayu Takeyama
- Subjects
musculoskeletal diseases ,Male ,endocrine system diseases ,Bone Neoplasms ,Logistic regression ,030226 pharmacology & pharmacy ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,medicine ,Electronic Health Records ,Humans ,Pharmacology (medical) ,Hypocalcaemia ,030212 general & internal medicine ,Risk factor ,Aged ,Retrospective Studies ,Pharmacology ,Receiver operating characteristic ,Bone Density Conservation Agents ,Hypocalcemia ,business.industry ,nutritional and metabolic diseases ,Retrospective cohort study ,Odds ratio ,Middle Aged ,medicine.disease ,Confidence interval ,Denosumab ,Logistic Models ,Case-Control Studies ,Female ,business ,Algorithm ,Algorithms ,medicine.drug - Abstract
WHAT IS KNOWN AND OBJECTIVE This study used electronic medical records to identify risk factors and establish a detection algorithm for denosumab-induced hypocalcaemia. METHODS We identified 201 patients with cancer who were initially prescribed denosumab. Hypocalcaemia was defined as an adjusted serum calcium level of ≤2.13 mmol/L. A diagnosis of denosumab-induced hypocalcaemia was confirmed by two physicians after reviewing patient medical records. We evaluated patient characteristics as potential screening factors. Moreover, a retrospective cohort study was conducted to identify risk factors for denosumab-induced hypocalcaemia. Odds ratios (ORs) were estimated using logistic regression analysis. RESULTS We analysed 164 patients with a low risk of hypocalcaemia. Among these, 29 (17.7%) patients were suspected to have denosumab-induced hypocalcaemia. The times to onset of definitive hypocalcaemia were shorter among these patients than among patients with non-denosumab-induced hypocalcaemia. Based on receiver operating characteristic curve analysis, we used time to onset of hypocalcaemia of ≤90 days as a second screening factor. The positive predictive value of this factor was 87.5%. In the retrospective cohort study, a significant difference was observed among patients with serum alkaline phosphatase (ALP) levels of >5.95 μkat/L before initial prescription (P
- Published
- 2018
24. Is Dose Adjustment of Prednisolone Required in Patients With IgA Nephropathy During Rifampicin Treatment for Mycobacterium avium Complex Lung Disease?
- Author
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Takayuki Tsuji, Naro Ohashi, Nozomi Yoshikawa, Hideo Yasuda, Takafumi Naito, Junichi Kawakami, and Soichiro Nagata
- Subjects
Lung Diseases ,Male ,medicine.medical_specialty ,Prednisolone ,Antitubercular Agents ,Gastroenterology ,Nephropathy ,Dose adjustment ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Mycobacterium avium complex ,In patient ,Aged ,Mycobacterium avium-intracellulare Infection ,Pharmacology ,biology ,business.industry ,Glomerulonephritis, IGA ,Glomerulonephritis ,Middle Aged ,Mycobacterium avium Complex ,medicine.disease ,biology.organism_classification ,Lung disease ,Female ,Rifampin ,business ,Rifampicin ,medicine.drug - Published
- 2019
25. Validated LC-MS/MS Method for the Simultaneous Determination of Amlodipine and Its Major Metabolites in Human Plasma of Hypertensive Patients
- Author
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Reina Taguchi, Hikaru Sato, Junichi Kawakami, and Takafumi Naito
- Subjects
Calibration curve ,Formic acid ,Electrospray ionization ,Tandem mass spectrometry ,Mass spectrometry ,030226 pharmacology & pharmacy ,01 natural sciences ,Sensitivity and Specificity ,Matrix (chemical analysis) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Tandem Mass Spectrometry ,hemic and lymphatic diseases ,medicine ,Humans ,Pharmacology (medical) ,Amlodipine ,neoplasms ,Antihypertensive Agents ,Pharmacology ,Chromatography ,Molecular Structure ,010401 analytical chemistry ,0104 chemical sciences ,chemistry ,Hypertension ,medicine.drug ,Chromatography, Liquid - Abstract
BACKGROUND No information on the pharmacokinetic characteristics of amlodipine (AML) metabolites is available. This study aimed to develop a method based on isocratic liquid chromatography coupled to tandem mass spectrometry for the simultaneous determination of AML and its 2 major metabolites, dehydroamlodipine (DH-AML) and O-des[2-aminoethyl]-O-carboxymethyl DH-AML (CM-DH-AML), and to use it for monitoring this drug in hypertensive patients. METHODS Acetonitrile-deproteinized plasma specimens were separated using an octadecyl-silica column (3-μm particle size) with a mobile phase consisting of 50% methanol containing 0.15% of formic acid in water. The run time was 9 minutes. The mass spectrometer was run in the positive ion electrospray ionization mode. This method was applied for the determination of AML and its metabolites in plasma samples from patients treated with this drug. RESULTS The calibration curves in human plasma of AML, DH-AML, and CM-DH-AML were linear over the concentration ranges of 0.5-64, 1-64, and 0.5-64 ng/mL, respectively, and their lower limits of quantification were 0.5, 1, and 0.5 ng/mL, respectively. Their extraction recovery rates and matrix factors in human plasma were 94.8%-109.0% and 97.0%-101.4%, respectively. The intra-assay and interassay imprecisions and accuracies were within 10.8% and 95.4%-111.2%, respectively. The plasma concentration ranges of AML, DH-AML, and CM-DH-AML were 6.5-20.9, 1.4-10.9, and 5.6-38.3 ng/mL, respectively. CONCLUSIONS The present method with acceptable analytical performance can be helpful for monitoring the plasma concentration of AML, including the determination of its metabolites in patients with hypertension.
- Published
- 2017
26. Interindividual Variation of Pharmacokinetic Disposition of and Clinical Responses to Opioid Analgesics in Cancer Pain Patients
- Author
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Takafumi Naito and Junichi Kawakami
- Subjects
CYP2D6 ,ATP Binding Cassette Transporter, Subfamily B ,Palliative care ,Pharmaceutical Science ,Pharmacology ,Bioinformatics ,Fentanyl ,Neoplasms ,Cytochrome P-450 CYP3A ,Humans ,Medicine ,Precision Medicine ,Adverse effect ,Drug Substitution ,business.industry ,Palliative Care ,Genetic Variation ,Drug Tolerance ,Pain, Intractable ,Analgesics, Opioid ,Cytochrome P-450 CYP2D6 ,Opioid ,Pharmacogenetics ,business ,Cancer pain ,Oxycodone ,medicine.drug - Abstract
Use of prescription opioids for cancer pain according to the World Health Organization analgesic ladder has been accepted in Japan. Although oxycodone and fentanyl are commonly used as first-line analgesics, a few clinical reports have been published on interindividual variations in their pharmacokinetics and clinical responses in cancer patients. (1) Some factors relating to CYP2D6, CYP3A, ATP-binding cassette sub-family B member 1 (ABCB1), and opioid receptor mu 1 (OPRM1) involve oxycodone pharmacokinetics and sensitivity in humans. The relations between their genetic variations and clinical responses to oxycodone are being revealed in limited groups. In our study, the impact of genetic variants and pharmacokinetics on clinical responses to oxycodone were evaluated in Japanese populations. (2) Opioid switching improves the opioid tolerance related to the balance between analgesia and adverse effects. Some patients have difficulty in obtaining better opioid tolerance in recommended conversion ratios. The activities of CYP3A, ABCB1, and OPRM1 contribute to the interindividual variations in clinical responses to fentanyl in cancer patients. However, the variations in opioid switching remain to be clarified in clinical settings. In our study, genetic factors related to interindividual variations in clinical responses in opioid switching to fentanyl were revealed in Japanese populations. In this symposium review, the possibility of approaches to personalized palliative care using opioids based on genetic variants of CYP2D6, CYP3A5, ABCB1, and OPRM1 is discussed.
- Published
- 2015
27. Clinical Pharmacology and Pharmacoepidemiology for Medication Safety in Clinical Settings
- Author
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Junichi Kawakami
- Subjects
Pharmacology ,medicine.medical_specialty ,Clinical pharmacology ,Gabapentin ,business.industry ,Pharmacoepidemiology ,Analgesic ,Pain ,Pharmaceutical Science ,Intestinal absorption ,law.invention ,Fentanyl ,Risk Factors ,law ,Neoplasms ,Relative risk ,Internal medicine ,Pharmacology, Clinical ,medicine ,Humans ,Pain Management ,business ,Oxycodone ,medicine.drug - Abstract
In this review, optimization of individualized analgesic therapy in cancer-pain patients (1), pharmacoepidemiological studies using a hospital database (DB) (2), and other clinical and practical research studies (3) were summarized. (1) The aim of the analgesic study was to evaluate individual factors in the effects of pain-relief, and ADR of analgesics from the viewpoints of clinical pharmacokinetics and pharmacodynamics. Oxycodone, fentanyl, and gabapentin were used. For the dose escalation and ADR of oxycodone, the plasma disposition of noroxycodone regulated by CYP3A5 polymorphisms and cancer cachexia were found to be individual factors. The ADR and clinical response of fentanyl were affected by polymorphisms of CYP3A5 and ABCB1. In the pharmacokinetics of gabapentin, concomitant magnesium oxide reduced the intestinal absorption of gabapentin. (2) The aim of the DB study was to demonstrate a pharmacoepidemiological advantage using a hospital DB of a million-scale for post-marketing safety management. We tried to detect fluoroquinolone (FQ)-induced tendon disorders, because its risk ratio in Japan has not been clarified. The risk of a tendon disorder in FQ-prescribed patients was 0.082% (95%CI: 0.049-0.137%), and significantly higher than that in cephalosporin-prescribed patients. The risk ratio in FQ-prescribed patients in relation to cephalosporin-prescribed patients was 6.29 (95%CI: 2.27-17.46). (3) Individual variation of plasma exposure of free linezolid and its ratio to minimum inhibitory concentration in critically ill patients, as well as three other studies, were described. In conclusion, our achievement in accurately assessing these would contribute to medication safety and the appropriate use of medicines in clinical settings.
- Published
- 2015
28. Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients
- Author
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Junichi Kawakami, Takafumi Naito, Yasuaki Mino, and Takahiro Yamada
- Subjects
Male ,Antifungal Agents ,Itraconazole ,CYP3A ,Clinical Biochemistry ,Triazole ,Inflammation ,Pharmacology ,Biochemistry ,Immunocompromised Host ,chemistry.chemical_compound ,Pharmacokinetics ,medicine ,Humans ,Glucocorticoids ,Aged ,Voriconazole ,business.industry ,Biochemistry (medical) ,General Medicine ,Middle Aged ,chemistry ,Prednisolone ,Female ,medicine.symptom ,business ,Glucocorticoid ,medicine.drug - Abstract
Background The expression of hepatic CYP3A decreases with inflammatory response but increases with glucocorticoid administration. The aim of this study was to evaluate the plasma concentration of voriconazole and itraconazole under inflammatory conditions and glucocorticoid therapy. Methods Forty-one voriconazole- and 42 itraconazole-treated immunocompromised patients were enrolled in this study. Plasma concentrations of triazoles and their major metabolites at 12 h after dosing were determined. The relationships between C-reactive protein (CRP), prednisolone dose, and plasma exposure parameters of triazole were evaluated. Results Plasma concentration of voriconazole was not correlated with that of its N-oxide. A higher CRP was correlated with a higher dose-normalized plasma concentration of voriconazole and a lower plasma concentration ratio of N-oxide to voriconazole. Prednisolone dose was weakly correlated with the plasma concentration ratio of N-oxide to voriconazole. Plasma concentration of itraconazole had a good correlation with that of its hydroxide. Parameters of itraconazole were not associated with CRP and prednisolone dose. Conclusions An inflammatory state raised the plasma concentration of voriconazole through its metabolic reduction, while it did not have an effect on plasma concentration of itraconazole. Concomitant glucocorticoid administration slightly elevated the voriconazole metabolism, although it did not affect the plasma concentration of triazoles.
- Published
- 2015
29. Saturated Metabolism of Voriconazole N-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses
- Author
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Tatsuya Yagi, Takafumi Naito, Yasuaki Mino, Takahiro Yamada, and Junichi Kawakami
- Subjects
Pharmacology ,Voriconazole ,Nonlinear pharmacokinetics ,Metabolite ,Pharmaceutical Science ,Oxidation reduction ,General Medicine ,Metabolism ,chemistry.chemical_compound ,Pharmacokinetics ,chemistry ,Plasma concentration ,medicine ,N oxidation ,medicine.drug - Abstract
Metabolic saturation of voriconazole based on the trough plasma concentrations of voriconazole and its major metabolite N-oxide were evaluated according to CYP2C19 genotypes in 58 Japanese patients receiving voriconazole (median dose; 200 mg twice daily) for prophylaxis or treatment. Predose trough plasma concentrations of voriconazole and N-oxide were monitored on day 5 d or later after initiation of voriconazole treatment. Large interindividual variations in trough plasma concentrations of voriconazole and N-oxide were observed. Dose-normalized trough plasma concentrations of voriconazole were strongly correlated with its absolute trough concentrations, and the straight regression line between them intersected close to the origin of the coordinates. No significant correlation was observed between the trough plasma concentrations of voriconazole and N-oxide. The inverse value of the metabolic ratio of N-oxide to voriconazole was strongly correlated with the absolute trough voriconazole concentrations. No significant differences in the trough plasma concentrations of voriconazole and N-oxide or the metabolic ratio of N-oxide to voriconazole between the CYP2C19 genotypes were observed. Saturated metabolism of voriconazole N-oxidation rather than CYP2C19 genotypes contributed to the nonlinear pharmacokinetics. The metabolic process converting voriconazole to N-oxide was saturated at the clinical dose.
- Published
- 2015
30. Simultaneous determination of erlotinib and its isomeric major metabolites in human plasma using isocratic liquid chromatography-tandem mass spectrometry and its clinical application
- Author
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Takafumi Naito, Junichi Kawakami, and Takuya Ishida
- Subjects
Pharmacology ,Analyte ,Chromatography ,Chemistry ,Calibration curve ,Clinical Biochemistry ,General Medicine ,Mass spectrometry ,Biochemistry ,respiratory tract diseases ,Analytical Chemistry ,chemistry.chemical_compound ,Liquid chromatography–mass spectrometry ,Human plasma ,Drug Discovery ,medicine ,Particle size ,Erlotinib ,Acetonitrile ,Molecular Biology ,medicine.drug - Abstract
This study developed a method for the simultaneous determination of erlotinib and its isomeric major metabolites, OSI-413 and OSI-420, in human plasma using an isocratic liquid chromatography–tandem mass spectrometry. Plasma specimens deproteinized with acetonitrile were separated using a 3-µm particle size octadecylsilyl column. The m/z values of the precursor and product ions for the analytes were as follows: erlotinib, 394.2/278.2; and OSI-413 and OSI-420, 380.2/278.2. The total run time was 21 min and no peaks interfering with the analytes and internal standard (d6-erlotinib) in human plasma were observed. The calibration curves of erlotinib, OSI-413 and OSI-420 were linear over the concentration ranges of 10–3000, 2–500 and 2–100 ng/mL, respectively. The pretreatment recovery ratios were >86.1%. The intra- and inter-assay precisions and accuracies were
- Published
- 2014
31. Blood distribution of bortezomib and its kinetics in multiple myeloma patients
- Author
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Kazunori Ohnishi, Hiroshi Yamada, Takafumi Naito, Takashi Osawa, Junichi Kawakami, Yasuaki Mino, and Takanori Kaneko
- Subjects
Adult ,Male ,Combination therapy ,Clinical Biochemistry ,Pharmacology ,Dexamethasone ,Bortezomib ,Plasma ,Pharmacokinetics ,immune system diseases ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Distribution (pharmacology) ,cardiovascular diseases ,neoplasms ,Multiple myeloma ,Aged ,medicine.diagnostic_test ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Boronic Acids ,Discontinuation ,Therapeutic drug monitoring ,Pyrazines ,Erythrocyte Count ,Female ,Multiple Myeloma ,business ,medicine.drug - Abstract
Objectives Pharmacokinetic disposition of bortezomib in the blood has not been fully characterized in humans. This study aimed to evaluate the blood distribution of bortezomib and its kinetics in multiple myeloma patients. Design and method Eighteen multiple myeloma patients receiving bortezomib–dexamethasone combination therapy were enrolled. Blood specimens were drawn just before bortezomib administration on days 1 and 8 in the second and third cycles and after discontinuation. The relationships between bortezomib concentration and blood components were evaluated. Results Bortezomib concentration in the blood on day 1 was higher than that on day 8 in the second cycle. No difference was observed in bortezomib blood concentrations between day 8 in the second and third cycles. The bortezomib concentration in the blood and blood cells was 3- and 7-fold higher than that in plasma. Bortezomib concentration in the blood was correlated with the red blood cell count. The half-life of bortezomib in the blood was 23 days. Conclusion Bortezomib was taken up into red blood cells to only a limited extent and eliminated in parallel to the red blood cells' lifespan. The turnover of red blood cells can affect the pharmacokinetic disposition of bortezomib in multiple myeloma patients.
- Published
- 2014
32. Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients
- Author
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Masaki Tashiro, Junichi Kawakami, Yoshiyuki Kagawa, and Takafumi Naito
- Subjects
Male ,Cytochrome ,Genotype ,Clinical Biochemistry ,Pharmacology ,030226 pharmacology & pharmacy ,Prochlorperazine ,03 medical and health sciences ,0302 clinical medicine ,Cytochrome P-450 Enzyme System ,Dopamine receptor D2 ,Neoplasms ,medicine ,Humans ,Aged ,biology ,business.industry ,Antagonist ,Cytochrome P450 ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Prolactin ,030220 oncology & carcinogenesis ,biology.protein ,Antiemetics ,Dopamine Antagonists ,Female ,business ,medicine.drug - Abstract
Background Oral prochlorperazine, a dopamine D2 receptor antagonist, is largely metabolized to sulphoxide, 7-hydroxylate and N-desmethylate by cytochrome P450s (CYPs). This study evaluated the influence of CYP genotype on the plasma dispositions of prochlorperazine and its metabolites and their relationships with antiemetic efficacy and prolactin elevation in cancer patients. Methods Forty-eight cancer patients treated with oral prochlorperazine were enrolled. Plasma prochlorperazine and its metabolites concentrations and serum prolactin concentration were determined at 12 h after the evening dosing. The genotypes of CYP2C19, CYP2D6 and CYP3A5 and the incidences of nausea and vomiting were investigated. Results The plasma concentrations of the prochlorperazine metabolites were weakly correlated with that of the parent drug. The CYP genotypes did not affect the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine and its metabolites were not associated with the incidences of nausea and vomiting. The incidence of vomiting was significantly higher in females than in males. The serum prolactin concentration was weakly correlated with the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine metabolites rather than the parent drug had a weaker relation to serum prolactin concentration. Conclusions The CYP genotypes did not affect the plasma dispositions of prochlorperazine and its metabolites. The prochlorperazine metabolites did not have a strong effect on antiemetic efficacy, while they were slightly associated with prolactin secretion in cancer patients.
- Published
- 2017
33. An algorithm for the identification of heparin-induced thrombocytopenia using a medical information database
- Author
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Masahiro Tohkin, Katsuhito Hori, Kimie Sai, Michio Kimura, Yoshiro Saito, Junichi Kawakami, Katsunori Segawa, and Tadaaki Hanatani
- Subjects
Male ,Databases, Factual ,computer.software_genre ,Logistic regression ,Pharmacovigilance ,Risk Factors ,Heparin-induced thrombocytopenia ,medicine ,Humans ,Pharmacology (medical) ,Medical diagnosis ,Risk factor ,Aged ,Pharmacology ,Database ,Heparin ,business.industry ,Medical record ,Odds ratio ,medicine.disease ,Thrombocytopenia ,Identification (information) ,Female ,business ,computer ,Algorithm ,Algorithms - Abstract
Summary What is known and objective Using effective algorithms for extracting relevant drug and patient information from electronic medical information data systems is likely to form an increasingly important aspect of pharmacovigilance. To this end, we aimed to develop and validate a novel algorithm for detecting heparin-induced thrombocytopenia (HIT) using a medical information database (MID) and for identifying possible risk factors for HIT. Methods We developed a new algorithm for detecting HIT based on platelet count at distinct time-points and diagnostic information from patients treated with unfractionated heparin (UFH) from April 2008 through March 2012 at Hospital of Hamamatsu University School of Medicine, Japan. Definitive diagnoses of HIT were made through reviews of the medical records by a skilled haematologist. The performance of the algorithm was assessed using the positive predictive value (PPV). Multivariate logistic regression analysis was used to identify possible risk factors for HIT. Results and discussion This algorithm detected 47 patients with suspected HIT in the source population (n = 2875). Of these, 41 were identified as patients with definitive HIT after review of the medical records. The PPV for the algorithm was 87·2%, and the frequency of definitive HIT was 1·4%. Longer-term treatment (≥4 days) with UFH was identified as a risk factor for HIT, with an odds ratio of 5·38 (95% CI: 2·35–12·32) for definitive HIT. What is new and conclusion We developed a novel, high-PPV detection algorithm for HIT and identified longer-term treatment with UFH as a risk factor for HIT. Our results support the utility of MIDs for improving pharmacovigilance.
- Published
- 2013
34. Cancer Cachexia Raises the Plasma Concentration of Oxymorphone Through the Reduction of CYP3A But Not CYP2D6 in Oxycodone-Treated Patients
- Author
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Masaki Tashiro, Takafumi Naito, Junichi Kawakami, Kazunori Ohnishi, and Takuya Ishida
- Subjects
Pharmacology ,business.industry ,Incidence (epidemiology) ,medicine.disease ,Cachexia ,Pharmacokinetics ,Oxymorphone ,Anesthesia ,Vomiting ,Medicine ,Pharmacology (medical) ,medicine.symptom ,business ,Cancer pain ,Adverse effect ,Oxycodone ,medicine.drug - Abstract
This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence.
- Published
- 2013
35. Hydroxy-itraconazole pharmacokinetics is similar to that of itraconazole in immunocompromised patients receiving oral solution of itraconazole
- Author
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Takayuki Watanabe, Hiroshi Yamada, Tatsuya Yagi, Yasuaki Mino, Takahiro Yamada, Takafumi Naito, and Junichi Kawakami
- Subjects
Male ,Antifungal Agents ,Itraconazole ,Metabolite ,Clinical Biochemistry ,Serum albumin ,Administration, Oral ,Renal function ,Pharmacology ,Biochemistry ,Drug Administration Schedule ,Immunocompromised Host ,chemistry.chemical_compound ,Pharmacokinetics ,Tandem Mass Spectrometry ,medicine ,Humans ,Serum Albumin ,Active metabolite ,Aged ,biology ,Biochemistry (medical) ,Albumin ,General Medicine ,Middle Aged ,Solutions ,Mycoses ,chemistry ,Hematologic Neoplasms ,Plasma concentration ,biology.protein ,Female ,Chromatography, Liquid ,Glomerular Filtration Rate ,Immunoproliferative Disorders ,medicine.drug - Abstract
The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole (ITZ), is not fully known.Oral solution of ITZ was administered in 46 immunocompromised patients as a single 200 mg dose for at least 12 days. The plasma concentrations of ITZ, active OH-ITZ, and keto-itraconazole (keto-ITZ), an inactive metabolite, 12 h after administration were determined by LC-UV or LC-MS/MS.The mean±SD of plasma concentrations of ITZ, OH-ITZ, and keto-ITZ were 833±468, 798±454, and 3.94±2.68 μg/l, respectively. A greater correlation coefficient was observed between plasma concentrations of ITZ and OH-ITZ (r=0.90, P0.01) than between OH-ITZ and keto-ITZ (r=0.44, P0.01). Plasma concentration of OH-ITZ was inversely correlated with concentration ratio of keto-ITZ to OH-ITZ (r=-0.52, P0.01). Plasma concentrations of ITZ and OH-ITZ were correlated with serum concentration of albumin (r=0.36, P=0.01 and r=0.37, P=0.01) and estimated glomerular filtration rate (r=-0.27, P=0.08 and r=-0.35, P=0.02).The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-ITZ, serum concentration of albumin, and renal function in immunocompromised patients. The plasma concentration of OH-ITZ was strongly correlated with that of ITZ. Prevention of fungal infections can be improved by determining the plasma concentration of ITZ or OH-ITZ.
- Published
- 2013
36. Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time
- Author
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Shinya Motohashi, Junichi Kawakami, Katsuhito Hori, Hiroyuki Mineta, Seiji Hosokawa, Hiroshi Furuse, Seiichiro Ozono, Yasuaki Mino, and Takafumi Naito
- Subjects
Male ,Bilirubin ,Morpholines ,medicine.medical_treatment ,Coefficient of variation ,Pharmaceutical Science ,Antineoplastic Agents ,Pharmacology ,chemistry.chemical_compound ,Pharmacokinetics ,Interquartile range ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Aprepitant ,Aged ,Cisplatin ,Chemotherapy ,Univariate analysis ,Polymorphism, Genetic ,business.industry ,General Medicine ,Middle Aged ,chemistry ,Area Under Curve ,Female ,business ,medicine.drug - Abstract
The pharmacokinetics of aprepitant, a neurokinin-1 receptor antagonist, have not been fully evaluated in clinical settings. The aim of this study was to characterize the plasma pharmacokinetics of aprepitant and reveal their influence of laboratory tests and cytochrome P450 (CYP) 3A5 gene polymorphisms in cancer patients. Forty-four Japanese cancer patients receiving cisplatin-based chemotherapy for the first time following oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) were enrolled. The patients did not have gastrointestinal disease and the clinical laboratory values were within their normal reference levels. The plasma concentrations of aprepitant 24 (day 2 predose), 72, and 120 h after the first aprepitant administration were determined using LC-MS/MS. The relationships between plasma exposure to aprepitant and body weight, clinical laboratory values, age, gender, or CYP3A5*3 were investigated. The median and interquartile ranges of the 120-h area under the plasma concentration time curve (AUC)(0-120) of aprepitant were 73215 and 55518-91121 ng h/mL. The coefficient of variation value for aprepitant AUC(0-120) was 53%. The AUC(0-120) of aprepitant was correlated with the levels of total bilirubin and serum albumin, respectively (r=0.454, p
- Published
- 2013
37. Development of a novel algorithm for detecting glucocorticoid-induced diabetes mellitus using a medical information database
- Author
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Katsunori Segawa, Junichi Kawakami, Michio Kimura, Takuya Imatoh, Katsuhito Hori, Kimie Sai, and Yoshiro Saito
- Subjects
Adult ,Male ,Databases, Factual ,Prednisolone ,030209 endocrinology & metabolism ,Medical information ,computer.software_genre ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,medicine ,Diabetes Mellitus ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Aged ,Pharmacology ,Glycated Hemoglobin ,Database ,Receiver operating characteristic ,business.industry ,Medical record ,Pharmacoepidemiology ,Middle Aged ,University hospital ,medicine.disease ,Female ,business ,computer ,Algorithm ,Glucocorticoid ,Algorithms ,medicine.drug - Abstract
SummaryWhat is known and objective Glucocorticoid-induced diabetes mellitus (GIDM) increases the risk of diabetes mellitus (DM)-related complications but is generally difficult to detect in clinical settings. The criteria for diagnosing GIDM have not been established. Recently, medical information databases (MIDs) have been used in post-marketing surveillance (PMS) studies. We conducted a pharmacoepidemiological study to develop an algorithm for detecting GIDM using MID. Methods We selected 1214 inpatients who were newly prescribed with a typical glucocorticoid, prednisolone, during hospitalization from 2008 to 2014 from an MID of Hamamatsu University Hospital in Japan. GIDM was screened based on fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) levels according to the current Japan Diabetes Society (JDS) DM criteria, and its predictability was evaluated by an expert's review of medical records. We investigated further candidate screening factors using receiver operating characteristics analysis. Results Sixty-three inpatients were identified by the JDS DM criteria. Of these, 33 patients were definitely diagnosed as having GIDM by expert's review (positive predictive value = 52·4%). To develop a highly predictive algorithm, we compared the characteristics of inpatients diagnosed with definite GIDM and those diagnosed as non-GIDM. The maximum levels of HbA1c in patients with GIDM were significantly higher than those of patients with non-GIDM (66·9 mmol/mol vs. 58·7 mmol/mol, P < 0·001). The patients with GIDM had significantly higher relative increase in maximum level of HbA1c (RIM-HbA1c) than those with non-GIDM (0·3 vs. 0·03, P < 0·001). However, we did not observe a significant difference in those of fasting blood glucose (FBG) levels. We applied the RIM-HbA1c as a second screening factor to improve the detection of GIDM. It showed that a 13% increase in RIM-HbA1c separated patients with from patients without GIDM. What is new and conclusions Patients with GIDM had significantly higher RIM-HbA1c than patients with non-GIDM. There was a 13% increase in RIM-HbA1c in patients with GIDM compared to the others. Our detection algorithm for GIDM using an MID achieved high sensitivity and specificity, and was superior to one based only on the current JDS DM criteria. Our results suggest that monitoring changes in HbA1c levels is important for detecting GIDM and adds to current diagnostic criteria for type 2 DM.
- Published
- 2016
38. Trends in Non-prescription Drug Recalls in Japan
- Author
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Junichi Kawakami, Chikoto Yamamoto, Takuya Ishida, Takafumi Naito, and Takashi Osawa
- Subjects
Pharmacology ,Drug ,medicine.medical_specialty ,Time Factors ,Drug Industry ,business.industry ,media_common.quotation_subject ,Pharmaceutical Science ,Nonprescription Drugs ,Self Medication ,Legislation, Drug ,Human health ,Government Agencies ,Japan ,Topical agents ,Family medicine ,Therapeutic Categories ,medicine ,Non prescription ,Christian ministry ,Drug Recalls ,business ,Drug recall ,media_common - Abstract
Recalls of non-prescription drugs can contribute to preventing harm to human health, however, they also interrupt the supply of medicines to the market. The aim of the present study was to investigate the trends in non-prescription drug recalls in Japan. Class I, II, and III recalls reported from April 2009 to March 2014 were obtained from the websites of the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency. Each drug recall was classified according to year, dosage form, therapeutic category, and reasons for the recall. The trends over the 5 year period were assessed for each class. A total of 220 recalls were reported in the 5-year study period. The numbers of drug recalls were 21, 16, 80, 58, and 45 in 2009, 2010, 2011, 2012, and 2013, respectively. The drugs recalled consisted of 177 internal medications, 35 topical agents, and 8 others. Drug recalls were observed in 12 therapeutic categories of drug effects. The largest number of recalls was for Chinese herbal medicines and crude drugs. Of all the drug recalls in 2011, Chinese herbal medicines and crude drugs produced by one manufacturer accounted for 84%. Slightly more than half (54%) of drug recalls were due to a violation of the regulations. One manufacturer recalled many drugs because of non-compliance with the standard regulations for manufacturing drugs after 2011. In conclusion, non-prescription drug recalls can occur for any drug regardless of the dosage form and therapeutic category.
- Published
- 2016
39. Relationship between the plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain
- Author
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Hikaru Sato, Junichi Kawakami, Takafumi Naito, and Takuya Ishida
- Subjects
Male ,medicine.medical_specialty ,Genotype ,Pharmaceutical Science ,Pharmacology ,030226 pharmacology & pharmacy ,Fentanyl ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,polycyclic compounds ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Pharmacology (medical) ,CYP3A5 ,Aged ,Sex Characteristics ,business.industry ,Cancer ,Cancer Pain ,Middle Aged ,medicine.disease ,Hydroxycholesterols ,Analgesics, Opioid ,Endocrinology ,030220 oncology & carcinogenesis ,lipids (amino acids, peptides, and proteins) ,Female ,4β hydroxycholesterol ,Cancer pain ,business ,Sex characteristics ,medicine.drug - Abstract
This study aimed to evaluate the relationship between the concentrations of plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in cancer patients. Thirty-three Japanese cancer patients treated with transdermal fentanyl were enrolled. The concentrations of plasma fentanyl and norfentanyl, and serum 4β-hydroxycholesterol and total cholesterol were determined at day 8 or later after starting the medication. The plasma fentanyl concentration was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. The *3/*3 group had a lower metabolic ratio of fentanyl. The serum 4β-hydroxycholesterol concentration and its ratio to total cholesterol were significantly lower in the CYP3A5*3/*3 group than in the *1 allele carrier group. The concentrations of plasma fentanyl and serum 4β-hydroxycholesterol were significantly higher in women than in men. Gender did not affect the metabolic ratio of fentanyl or the concentration ratio of 4β-hydroxycholesterol. The plasma fentanyl concentration was not correlated with the serum 4β-hydroxycholesterol concentration, while the metabolic ratio of fentanyl was slightly correlated with the serum concentration ratio of 4β-hydroxycholesterol. In conclusion, CYP3A5*3 and gender affected the plasma fentanyl and serum 4β-hydroxycholesterol concentrations in cancer patients. However, the plasma disposition of fentanyl was not determined using the serum 4β-hydroxycholesterol concentration.
- Published
- 2016
40. Simultaneous determination of prochlorperazine and its metabolites in human plasma using isocratic liquid chromatography tandem mass spectrometry
- Author
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Junichi Kawakami, Masaki Tashiro, Takafumi Naito, and Yoshiyuki Kagawa
- Subjects
Pharmacology ,Chromatography ,medicine.drug_class ,Calibration curve ,Metabolite ,Clinical Biochemistry ,General Medicine ,Prochlorperazine ,Mass spectrometry ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Pharmacokinetics ,Human plasma ,Liquid chromatography–mass spectrometry ,Drug Discovery ,medicine ,Antiemetic ,Molecular Biology ,medicine.drug - Abstract
Oral prochlorperazine (PCZ), an antiemetic, undergoes extensive first-pass metabolism. The study developed a simultaneous analytical method for PCZ and its major metabolites, prochlorperazine sulfoxide (PCZSO), N-demethylprochlorperazine (NDPCZ) and 7-hydroxyprochlorperazine (PCZOH), in human plasma using an isocratic liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Deproteinized plasma specimens were separated using a 3 µm particle size octadecylsilyl column, and the run time was 10 min. The calibration curves were linear over the concentration ranges of 0.01-40 µg/L for PCZ, NDPCZ and PCZOH, and 0.05-80 µg/L for PCZSO. The intra- and inter-assay precisions and accuracies were within 7.0 and 99-104% and within 9.0 and 99-105%, respectively. The lower limits of quantification in human plasma were 10 ng/L for PCZ, NDPCZ and PCZOH, and 50 ng/L for PCZSO. The validated method was applied to the determination of plasma samples in 37 cancer patients receiving PCZ. Large interindividual variations were observed in plasma concentrations of PCZ, PCZSO, NDPCZ and PCZOH (relative standard deviation, 89.4, 88.7, 86.4 and 78.2%, respectively). In conclusion, this simultaneous LC-MS/MS method with acceptable analytical performance can be helpful for evaluating the pharmacokinetics of PCZ, including the determination of its metabolites in cancer patients and in clinical research.
- Published
- 2011
41. Effective plasma concentrations of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in the remission-maintenance phase
- Author
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Junichi Kawakami, Noriyoshi Ogawa, Yasuaki Mino, Takafumi Naito, and Kumiko Shimoyama
- Subjects
Pharmacology ,medicine.medical_specialty ,Lupus erythematosus ,Chemistry ,Albumin ,Mycophenolate ,medicine.disease ,Gastroenterology ,Mycophenolic acid ,Therapeutic index ,Pharmacokinetics ,Interquartile range ,Internal medicine ,medicine ,Prednisolone ,Pharmacology (medical) ,medicine.drug - Abstract
Summary What is known and Objective: Mycophenolate mofetil (MMF) has been reported recently to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) in SLE in the remission-maintenance phase remains to be clarified. The aim of this study was to evaluate the therapeutic efficacy of MMF and predose plasma concentrations of MPA and its phenolic glucuronide (MPAG) in patients with SLE in the remission-maintenance phase. Methods: Thirty-one patients with SLE receiving a fixed dosage regimen of MMF (median and interquartile range, 1500 and 1000–2000 mg/day) for at least 1 month and who had not experienced any adverse drug reactions for more than 3 months were enrolled. Results: Significant improvement was observed after MMF administration in total haemolytic complement CH50 and its fractions C3 and C4, immunoglobulins IgG, IgA and IgM, anti-dsDNA antibody, serum concentration of albumin and red blood cell count, even though the mean daily dose of prednisolone was significantly reduced (P = 0·02). Median predose plasma concentrations of MPA and MPAG were 1·95 and 26·2 μg/mL (interquartile ranges, 0·94–2·96 and 18·6–53·7 μg/mL). Predose plasma concentrations of MPA and MPAG correlated significantly with MMF dose (r = 0·64, P
- Published
- 2011
42. Cyclosporine alters correlation between free and total mycophenolic acid in kidney transplant recipients in the initial phase
- Author
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Atsushi Otsuka, Junichi Kawakami, Yasuaki Mino, Yoshiyuki Kagawa, Tatsuya Takayama, Seiichiro Ozono, and Takafumi Naito
- Subjects
Pharmacology ,medicine.medical_specialty ,Kidney ,Chemistry ,Urology ,Ciclosporin ,medicine.disease ,Mycophenolic acid ,Tacrolimus ,Calcineurin ,medicine.anatomical_structure ,Biochemistry ,Pharmacokinetics ,Free fraction ,medicine ,Pharmacology (medical) ,Kidney transplantation ,medicine.drug - Abstract
Summary What is known and Objective: The factors affecting the pharmacokinetics of free mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) are still unclear. The aim of this study was to evaluate the influence of cyclosporine on the pharmacokinetics of free MPA and MPAG. Methods: Seventy-seven kidney transplant recipients (23 were in an initial phase and 54 in a stable phase; 41 were treated with cyclosporine and 36 with tacrolimus) were enrolled. Free and total MPA and MPAG were determined using HPLC. The correlations between free and total predose concentrations (C0) of MPA or MPAG were evaluated separately in patients receiving calcineurin inhibitor medications. Results and Discussion: Serum concentration of albumin was lower in the initial phase than in the stable phase. A higher ratio of free MPAG C0 to free MPA C0 was observed in cyclosporine-treated than tacrolimus-treated kidney transplant recipients. Free MPA C0 correlated weakly with total MPA C0 in kidney transplant recipients treated with cyclosporine in the initial phase (ρ = 0·53, P = 0·06). What is new and Conclusion: Cyclosporine increased the ratio of free MPAG C0 to free MPA C0 and varied the free fraction of MPA in the hypoalbuminaemic kidney transplant recipients in the initial phase.
- Published
- 2011
43. Rapid and validated fluorometric HPLC method for determination of gabapentin in human plasma and urine for clinical application
- Author
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Yasuaki Mino, Kazuo Umemura, Yoshiaki Takashina, Junichi Kawakami, Takafumi Naito, and Tatsuya Yagi
- Subjects
Pharmacology ,Chromatography ,Gabapentin ,Calibration curve ,Urine ,High-performance liquid chromatography ,chemistry.chemical_compound ,Pharmacokinetics ,chemistry ,Human plasma ,medicine ,Pharmacology (medical) ,Hplc method ,Derivatization ,medicine.drug - Abstract
Summary What is known and Objective: A rapid derivatization and validated HPLC method for gabapentin in human plasma and urine is needed for clinical use. The objective of this study was to establish a rapid and validated analytical method for the determination of gabapentin in human plasma and urine using isocratic fluorometric HPLC for clinical application. Methods: This analytical method is based on precolumn fluorescent derivatization using 4-fluoro-7-nitro-benzofurazan. The derivatization was coupled to fast HPLC separation using a 2·3 μm-particle size ODS column (100 × 4·6 mm i.d.). Results and Discussion: The derivatization of gabapentin was optimized and HPLC separation was achieved over an ODS column with a run time of 3·5 min. Calibration curves in human plasma and urine were linear over the concentration ranges of 0·05–10 and 10–1000 μg/mL, respectively. Intra- and inter-assay precision and accuracy values of plasma were within 8·0% and 101–109% and within 8·3% and 94–108%, respectively. Those of urine were within 8·5% and 97–106% and within 9·5% and 97–105%, respectively. This validated method was applied to a pharmacokinetic study in healthy subjects. Interindividual variations in plasma disposition and urinary excretion of gabapentin were observed. What is new and Conclusion: A rapid and validated isocratic fluorometric HPLC method for the determination of gabapentin in human plasma and urine for clinical application has been established. This method can be utilized to evaluate the pharmacokinetic disposition of gabapentin in humans.
- Published
- 2011
44. Pharmacokinetic Variability of Mycophenolic Acid and Its Glucuronide in Systemic Lupus Erythematosus Patients in Remission Maintenance Phase
- Author
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Noriyoshi Ogawa, Yasuaki Mino, Takafumi Naito, Kumiko Shimoyama, and Junichi Kawakami
- Subjects
Adult ,Male ,medicine.medical_specialty ,Serum albumin ,Pharmaceutical Science ,Renal function ,Pharmacology ,Mycophenolate ,Gastroenterology ,Mycophenolic acid ,Glucuronides ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Lupus erythematosus ,biology ,business.industry ,General Medicine ,Middle Aged ,Mycophenolic Acid ,medicine.disease ,Free fraction ,Creatinine ,Prednisolone ,biology.protein ,Female ,business ,medicine.drug - Abstract
The aim of this study was to identify factors affecting the pharmacokinetics of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG) in systemic lupus erythematosus (SLE) patients. Thirty-one SLE patients in remission maintenance phase treated with mycophenolate mofetil (median 1500 mg/d) and prednisolone and followed-up for up to 56 months (median 13 months) were enrolled. Creatinine clearance and metal medication were significant predictors accounting for interindividual variability in the dose-normalized predose plasma concentration (C₀) of MPA (adjusted R²=0.305, p=0.01) in a multivariate analysis. Dose-normalized MPAG C₀ was significantly correlated with only creatinine clearance (adjusted R²=0.135, p=0.03). The free fraction of MPA was significantly correlated with only serum albumin (adjusted R²=0.700, p
- Published
- 2011
45. Surveillance of Workplace Contamination and Occupational Exposure to Antineoplastic Agents in a Hospital Setting: Establishment of a Monitoring Method Using Doxorubicin
- Author
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Takafumi Naito, Junichi Kawakami, Naoya Suzuki, Yoshiaki Takashina, Yasunori Miyamoto, Kazunori Ohnishi, Katsuhito Hori, and Keiji Matsumoto
- Subjects
medicine.medical_specialty ,Hospital setting ,Health Personnel ,Pharmaceutical Science ,Occupational safety and health ,Toxicology ,Occupational Exposure ,medicine ,Humans ,Monitoring methods ,Workplace ,Chromatography, High Pressure Liquid ,Pharmacology ,Antibiotics, Antineoplastic ,business.industry ,Guideline ,Contamination ,Hospitals ,Spot urine ,Chromatographic separation ,Doxorubicin ,Emergency medicine ,Occupational exposure ,Environmental Pollution ,business ,Environmental Monitoring - Abstract
An academic subcommittee of Japanese Society of Hospital Pharmacists formulated the guideline for the sterile preparation of antineoplastic agents in 2008. The practical methods to monitor a workplace contamination and occupational exposure to antineoplastic agents have not been introduced into a hospital setting yet. The aims of this study were to develop a monitoring method using doxorubicin for workplace contamination and occupational exposure to antineoplastic agents and to apply it to surveillance in a hospital setting. The surface contamination of workplace was wiped with non-woven fabric containing 70% 2-propanol. The occupational exposure was evaluated by spot urine sampling during 24 hours. Chromatographic separation was achieved by a reverse phase HPLC. Doxorubicin and fluorescein (internal standard) were detected at an excitation and emission wavelength of 470 and 550 nm, respectively. The monitoring method was applied to survey the workplace contamination and occupational exposure to antineoplastic agents in Hamamatsu University Hospital. The calibration curves for doxorubicin were linear over concentration ranges of 1.5-729 ng/100 cm(2) for surface contamination and 1.0-486 ng/ml for the urine. The run time was 10 min. The intra- and interassay precisions were within 8.5%. As the surveillance in a hospital setting, the flow line adhering to the guideline kept the exposure to low level. In addition, the occupational exposure in the workers was not observed. In conclusion, this study developed the monitoring method using doxorubicin for the workplace contamination and occupational exposure to antineoplastic agents. This method can be utilized to survey in a hospital setting.
- Published
- 2010
46. Onset of Clinical Effects and Plasma Concentration of Fluvoxamine in Japanese Patients
- Author
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Junichi Kawakami, Norio Mori, Shinya Uchida, Yasuhiro Katoh, Noriyuki Namiki, Hisakuni Hashimoto, Shizuo Yamada, Masayoshi Kawai, Noriyoshi Takei, and Yoshiyuki Kagawa
- Subjects
Adult ,Male ,Pharmaceutical Science ,Fluvoxamine ,Feeding and Eating Disorders ,Japan ,Hamd ,Humans ,Medicine ,Depression (differential diagnoses) ,Pharmacology ,Depressive Disorder ,Receiver operating characteristic ,Mood Disorders ,business.industry ,Maintenance dose ,Hamilton Rating Scale for Depression ,General Medicine ,Middle Aged ,Anxiety Disorders ,Antidepressive Agents ,Treatment Outcome ,ROC Curve ,Anesthesia ,Plasma concentration ,Antidepressant ,Female ,business ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
It is widely accepted that selective serotonin reuptake inhibitors (SSRIs) require 2 to 4 weeks of administration before improvements in emotional symptoms of depression are seen. We evaluated whether early monitoring of Hamilton Rating Scale for Depression (HAMD) scores in patients treated with the SSRI fluvoxamine could predict antidepressant response, and also assessed the relationship between the onset of clinical response following the start of fluvoxamine administration and its plasma concentration. Twelve depressed patients (baseline HAMD score ≥15) received an initial dose of fluvoxamine (50 mg/d) followed by an optimized maintenance dose according to their clinical symptoms after 7 d. HAMD scores and plasma drug concentrations were determined at 7 and 28 d after the first administration. There were 7 responders and 5 non-responders on day 28, as evaluated by HAMD scores. The HAMD score for the responders was significantly lower than that for the non-responders on day 7 (mean±S.D., 11.6±6.1 vs. 26.6±6.5, p=0.006). Thus, the reduction in HAMD score on day 7 was clearly divided between responders and non-responders. On day 28, the plasma concentration of fluvoxamine in responders was lower than that in non-responders (14.2±10.5 ng/ml vs. 44.2±28.1 ng/ml, p=0.051). Furthermore, receiver operating characteristic curve analysis conducted on day 28 revealed an upper concentration threshold of 28.2 ng/ml (p=0.042), with none in the responder group above that level. Our results suggest that HAMD score after the first week of treatment with fluvoxamine and the upper threshold of plasma drug concentration could predict whether a patient is a non-responder.
- Published
- 2010
47. Inosine monophosphate dehydrogenase activity depends on plasma concentrations of mycophenolic acid and its glucuronides in kidney transplant recipients
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Seiichiro Ozono, Junichi Kawakami, Atsushi Otsuka, Yoshiyuki Kagawa, Takafumi Naito, and Yasuaki Mino
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Adult ,Male ,Erythrocytes ,Clinical Biochemistry ,Serum albumin ,Pharmacology ,Mycophenolate ,Biochemistry ,Mycophenolic acid ,chemistry.chemical_compound ,Glucuronides ,IMP Dehydrogenase ,IMP dehydrogenase ,Lactate dehydrogenase ,medicine ,Humans ,Inosine-5′-monophosphate dehydrogenase ,Kidney transplantation ,Creatinine ,biology ,Chemistry ,Biochemistry (medical) ,General Medicine ,Middle Aged ,Mycophenolic Acid ,medicine.disease ,Kidney Transplantation ,biology.protein ,Female ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Inosine 5′-monophosphate dehydrogenase (IMPDH) is a target of the immunosuppressant mycophenolic acid (MPA) which is used for the prevention of acute rejection. We evaluated the concentration-dependent effects of MPA and its phenolic (MPAG) and acyl (AcMPAG) glucuronides on IMPDH activity in erythrocytes in an initial and a stable phase. Methods Eight kidney transplant recipients treated with mycophenolate mofetil (MMF) in an initial phase and 104 recipients [56 received MMF (MMF+) and 48 did not (MMF−)] in a stable phase were enrolled. Results IMPDH activity in erythrocytes was inhibited at the peak plasma concentration of MPA in initial kidney transplant recipients. However, median IMPDH activity in erythrocytes was 1.73 times higher in MMF+ than in MMF− kidney transplant recipients (38.7 to 22.4 nmol/g hemoglobin/h, P 12 ) of MPA, MPAG, and AcMPAG in stable kidney transplant recipients were 2.86, 49.9, and 0.256 μg/ml, respectively. In a multivariate analysis, AcMPAG C 12 , MPAG C 12 , MPA C 12 , serum creatinine, age, lactate dehydrogenase, and serum albumin were significant predictors, accounting for interindividual variability of IMPDH ( R 2 = 0.537, P = 0.02). Conclusion IMPDH activity in erythrocytes may be useful indicators of short-term immunosuppression and long-term exposure of MPA.
- Published
- 2009
48. Validated LC coupled to ESI-MS/MS analysis for fentanyl in human plasma and UV analysis in applied reservoir transdermal patches using a simple and rapid procedure
- Author
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Takafumi Naito, Yoshiaki Takashina, Yoshiyuki Kagawa, Junichi Kawakami, and Yasuaki Mino
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Spectrometry, Mass, Electrospray Ionization ,Calibration curve ,Analytical chemistry ,Absorption (skin) ,Administration, Cutaneous ,Dosage form ,Fentanyl ,Drug Stability ,Pharmacokinetics ,Neoplasms ,medicine ,Humans ,Pharmacology (medical) ,Solid phase extraction ,Transdermal ,Pharmacology ,Chromatography ,Chemistry ,Solid Phase Extraction ,Extraction (chemistry) ,Reproducibility of Results ,Pain, Intractable ,Calibration ,Spectrophotometry, Ultraviolet ,Chromatography, Liquid ,medicine.drug - Abstract
BACKGROUND AND OBJECTIVES: Fentanyl has been used for cancer pain in transdermal formulation. The aim of the present study was to establish an analytical method for fentanyl in human plasma and in an applied transdermal reservoir patch (Reservoir-TTS), as well as for therapeutic monitoring of fentanyl in cancer patients. METHOD: Electro-spray ionization mass spectrometric (ESI-MS/MS) analysis followed solid phase extraction (SPE) from human plasma and drug reservoir extraction from an applied Reservoir-TTS. Each separation was completed within 9 min using an ODS column (particle size, 3 microm, 2.0 mm i.d. x 75 mm) with 25% acetonitrile containing 5 mm ammonium acetate at pH 3.5. In the ESI-MS/MS analysis, the calibration curve for fentanyl was linear over a concentration range of 0.05-7.2 ng/mL in human plasma. The extraction efficiency of fentanyl in the human plasma was more than 95%. The intra- and interassay precision and accuracy were within 7% and 97.3-101.2%, respectively. The lower LOQ for fentanyl was 0.05 ng/mL in the human plasma. The extraction of the 25 microg/h and 50 microg/h Reservoir-TTS gave reproducible recoveries of 88.3% and 90.9%, respectively. The plasma concentration of fentanyl showed large interindividual variation in 31 patients with cancer pain. CONCLUSION: The method described is simple, accurate, and reproducible, and should be helpful for the therapeutic monitoring of fentanyl in cancer patients.
- Published
- 2009
49. [Untitled]
- Author
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Hiroshi YAMADA, Keiji MATSUMOTO, Masayuki SHIMIZU, Tasuku KUMAGAI, Takayuki WATANABE, Masayuki KINTSU, Mijong PARK, Kazuhiro KOSUGE, Junichi KAWAKAMI, and Keizo UMEGAKI
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Pharmacology ,Pharmacology (medical) - Published
- 2009
50. Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport
- Author
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Yoshikazu Yamamura, Tappei Takada, Junichi Kawakami, Hiroshi Suzuki, Isao Adachi, and Naoko Yoshida
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Pharmacology ,Abcg2 ,biology ,Swine ,Terpenes ,Vesicle ,Multidrug resistance-associated protein 2 ,fungi ,Pharmaceutical Science ,Sf9 ,Spodoptera ,Membrane transport ,Multidrug Resistance-Associated Protein 2 ,Terpenoid ,Neoplasm Proteins ,Biochemistry ,Mediated transport ,biology.protein ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Animals ,LLC-PK1 Cells ,ATP-Binding Cassette Transporters ,Efflux ,Multidrug Resistance-Associated Proteins - Abstract
The possibility of interactions between natural products/supplements and conventional prescription medicines is one of the most important issues in pharmacotherapeutic safety. Recently, we reported that some terpenoids such as (R)-(+)-citronellal and glycyrrhetic acid, which are present in herbal medicines, can act as inhibitors of P-glycoprotein (MDR1/ABCB1). In the present study, the effects of seven terpenoids on multidrug resistance-associated protein 2 (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2)-mediated transport were investigated in vitro. Membrane vesicles were prepared from MRP2 cDNA transfected Sf9 cells derived from pupal ovarian tissue of Spodoptera frugiperda, a fall armyworm, and BCRP cDNA transfected LLC-PK1 cells derived from porcine kidney. MRP2- or BCRP-mediated efflux transport was measured as ATP-dependent accumulation of [(3)H]estradiol 17-beta-d-glucuronide (E(2)17betaG) into membrane vesicles collected by a rapid filtration technique. The effects of (R)-(+)-citronellal, (S)-(-)-beta-citronellol, alpha-terpinene, terpinolene, (-)-beta-pinene, abietic acid, and glycyrrhetic acid on the intravesicular accumulation of [(3)H]E(2)17betaG were examined. Large decreases in the [(3)H]E(2)17betaG accumulation into vesicles from MRP2-overexpressing Sf9 cells were observed in the presence of glycyrrhetic acid and abietic acid, and their IC(50) values were about 20 and 51 microM, respectively. [(3)H]E(2)17betaG accumulation into vesicles from BCRP-overexpressing LLC-PK1 cells was suppressed by only glycyrrhetic acid, with an IC(50) value of about 39 microM. Other terpenoids used in this study did not alter the ATP-dependent accumulation of [(3)H]E(2)17betaG. These findings suggest that glycyrrhetic acid and abietic acid can potently inhibit MRP2- or BCRP-mediated membrane transport and may interact with their substrates in pharmacokinetic processes.
- Published
- 2008
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