37 results on '"Jang, Ji"'
Search Results
2. Exploring gender differences in pharmacokinetics of central nervous system related medicines based on a systematic review approach
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Lee, Seung-Min, Jang, Ji-Hun, and Jeong, Seung-Hyun
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- 2024
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3. Establishment of a fexofenadine population pharmacokinetic (PK)–pharmacodynamic (PD) model and exploration of dosing regimens through simulation
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Jang, Ji-Hun, Jeong, Seung-Hyun, and Lee, Yong-Bok
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- 2023
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4. Population pharmacokinetic modeling of levodropropizine: extended application to comparative analysis between commercial formulations and exploration of pharmacokinetic effects of diet.
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Jeong, Seung-Hyun, Jang, Ji-Hun, and Lee, Yong-Bok
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PHARMACOKINETICS ,BODY surface area ,HIGH-fat diet ,CHRONIC bronchitis ,ANTITUSSIVE agents - Abstract
Levodropropizine, a nonopioid antitussive agent, is being increasingly used in clinical practice with the development of several formulations for symptomatic relief of acute and chronic bronchitis. However, scientific and quantitative population pharmacokinetic analyses of levodropropizine are lacking. Moreover, no integrated quantitative comparison has been performed between formulations. This study quantitatively evaluated and predicted pharmacokinetic properties of formulations through population pharmacokinetic model–based comparisons of commercially available formulations. Plasma concentration profile results from bioequivalence studies of 60-mg immediate release (IR) levodropropizine tablets in 40 healthy Korean males were used as population pharmacokinetic modeling data. For interindividual variability in levodropropizine pharmacokinetics, body surface area was identified as an effective covariate that was positively correlated with peripheral compartment distribution volume. Population pharmacokinetic model for IR tablets well-described the levodropropizine syrup and capsule datasets, suggesting no significant differences in pharmacokinetics among IR tablets, syrups, and capsules of levodropropizine. In contrast, pharmacokinetic profiles differed between 90-mg controlled release (CR) and IR levodropropizine tablets; however, separate parameter estimation was possible by applying the same model structure. In terms of pharmacokinetics, twice-daily regimen of 90-mg CR tablets was equivalent to thrice-daily regimen of 60-mg IR tablets. However, at steady-state, interindividual plasma concentration variability within population was reduced by approximately 36.71–83.18%. For levodropropizine CR tablets, a high-fat diet significantly delayed gastrointestinal absorption but maintained overall plasma exposure equivalent. This study provides useful quantitative judgment data for precision medicine of levodropropizine and can be helpful in predicting the pharmacokinetics of levodropropizine based on commercialized formulation switching. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation.
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Kim, Yong-Kyun, Jo, Kyeong-Min, Lee, Jae-Ha, Jang, Ji-Hoon, Choe, Eun-Jun, Kang, Gaeun, Zang, Dae-Young, and Lee, Dong-Hwan
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KIDNEY physiology ,TEICOPLANIN ,CHILDREN with learning disabilities ,DRUG monitoring ,PHARMACOKINETICS ,DRUG dosage ,MONTE Carlo method - Abstract
In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations. [ABSTRACT FROM AUTHOR]
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- 2024
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6. A sensitive UPLC–ESI–MS/MS method for the quantification of cinnamic acid in vivo and in vitro: application to pharmacokinetic and protein binding study in human plasma
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, Oh, In-Joon, and Lee, Yong-Bok
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- 2020
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7. Gender differences in pharmacokinetics and tissue distribution of 4-n-nonylphenol in rats
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, and Lee, Yong-Bok
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- 2019
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8. Comparison of UPLC-MS/MS and HPLC-UV methods for the determination of zaltoprofen in human plasma
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Jang, Ji-Hun, Jeong, Seung-Hyun, Cho, Hea-Young, and Lee, Yong-Bok
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- 2019
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9. Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii.
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Lee, Dong-Hwan, Kim, Shin-Young, Kim, Yong-Kyun, Jung, So-Young, Jang, Ji-Hoon, Jang, Hang-Jea, and Lee, Jae-Ha
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CARBAPENEM-resistant bacteria ,VENTILATOR-associated pneumonia ,ACINETOBACTER baumannii ,COLISTIN ,PHARMACOKINETICS - Abstract
Colistimethate sodium (CMS) nebulization is associated with reduced systemic toxicity compared to intravenous injection, with potentially enhanced clinical efficacy. This study aimed to assess the pharmacokinetic (PK) properties of colistin during low-dose CMS nebulization in patients with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii. A nonlinear mixed-effects modeling approach was applied to develop population PK models for colistin in both epithelial lining fluid (ELF) and plasma. Twenty patients participated, and 80 ELF and 100 plasma samples were used for model development. Median colistin concentrations measured in ELF were 614-fold, 408-fold, and 250-fold higher than in plasma at 1, 3, and 5 h, respectively. Time courses in both ELF and plasma were best described by a one-compartment model with a Weibull absorption process. When the final model was simulated, the maximum free concentration and area under the free colistin concentration–time curve at steady state over 24 h in the plasma were approximately 1/90 and 1/50 of the corresponding values in ELF at steady state, respectively. For an A. baumannii MIC of 1 mg/L, inhaling 75 mg of CMS at 6 h intervals was deemed appropriate, with dose adjustments needed for MICs exceeding 2 mg/L. Using a nebulizer for CMS resulted in a notably higher exposure of colistin in the ELF than plasma, indicating the potential of nebulization to reduce systemic toxicity while effectively treating VAP. [ABSTRACT FROM AUTHOR]
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- 2024
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10. A population pharmacokinetic model of methotrexate in Korean patients with haematologic malignancy.
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Jung, Yun Seob, Son, Mijeong, Lee, Sang‐Guk, Chong, June‐Won, Kim, Soo‐Jeong, Jang, Ji Eun, Lyu, Chuhl Joo, Hahn, Seung Min, Han, Jung Woo, and Park, Kyungsoo
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KOREANS ,METHOTREXATE ,NON-Hodgkin's lymphoma ,PHARMACOKINETICS ,ACUTE leukemia - Abstract
Aims: This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with haematologic malignancy, identify factors affecting methotrexate PK, and propose an optimal dosage regimen for the Korean population. Methods: Data were retrospectively collected from 188 patients with acute leukaemia or non‐Hodgkin's lymphoma who were admitted to Severance Hospital during the period from November 2005 to January 2016. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. Results: A two‐compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.09 L for central volume of distribution (V1), 17.65 L for peripheral volume of distribution (V2), 12.89 L/h for clearance (CL) and 0.655 L/h for inter‐compartmental clearance in a 50 kg patient. Covariate analyses showed that, at the weight of 50 kg, CL decreased by 0.11 L/h for each 1‐year increase in age above 14 years old and decreased 0.8‐fold when serum creatinine level doubled, indicating the importance of age‐specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (= V1 + V2) was 0.85 L/kg, which was similar to those in the Western or Chinese populations. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. Conclusions: The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with haematologic malignancy. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Pharmacokinetic Analysis of Levodropropizine and Its Potential Therapeutic Advantages Considering Eosinophil Levels and Clinical Indications.
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Jang, Ji-Hun, Cho, Young-Jin, and Jeong, Seung-Hyun
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CLINICAL indications , *EOSINOPHILS , *COUGH , *BODY surface area , *PHARMACOKINETICS , *KOREANS - Abstract
Levodropropizine is a non-narcotic, non-centrally acting antitussive that inhibits the cough reflex triggered by neuropeptides. Despite the active clinical application of levodropropizine, the exploration of its inter-individual pharmacokinetic diversity and of factors that can interpret it is lacking. The purpose of this study was to explore effective covariates associated with variation in the pharmacokinetics of levodropropizine within the population and to perform an interpretation of covariate correlations from a therapeutic perspective. The results of a levodropropizine clinical trial conducted on 40 healthy Korean men were used in this pharmacokinetic analysis, and the calculated pharmacokinetic and physiochemical parameters were screened for effective correlations between factors through heatmap and linear regression analysis. Along with basic compartmental modeling, a correlation analysis was performed between the model-estimated parameter values and the discovered effective candidate covariates for levodropropizine, and the degree of toxicity and safety during the clinical trial of levodropropizine was quantitatively monitored, targeting the hepatotoxicity screening panel. As a result, eosinophil level and body surface area (BSA) were explored as significant (p-value < 0.05) physiochemical parameters associated with the pharmacokinetic diversity of levodropropizine. Specifically, it was confirmed that as eosinophil level and BSA increased, levodropropizine plasma exposure increased and decreased, respectively. Interestingly, changes in an individual's plasma exposure to levodropropizine depending on eosinophil levels could be interpreted as a therapeutic advantage based on pharmacokinetic benefits linked to the clinical indications for levodropropizine. This study presents effective candidate covariates that can explain the inter-individual pharmacokinetic variability of levodropropizine and provides a useful perspective on the first-line choice of levodropropizine in the treatment of inflammatory respiratory diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Modeling population pharmacokinetics of morniflumate in healthy Korean men: extending pharmacometrics analysis to niflumic acid, its major active metabolite.
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Jeong, Seung-Hyun, Jang, Ji-Hun, and Lee, Yong-Bok
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KOREANS ,PHARMACOKINETICS ,ACID analysis ,BODY mass index ,DRUG efficacy - Abstract
This study aimed to quantify and explain inter-subject variability in morniflumate pharmacokinetics and identify effective covariates through population pharmacokinetics modeling. Models were constructed using bioequivalence pharmacokinetics results from healthy Korean males and individual physiological and biochemical parameters. Additionally, we incorporated previously reported pharmacokinetics results of niflumic acid, a major active metabolite of morniflumate, to extend the established population pharmacokinetics model and predict niflumic acid pharmacokinetics. Moreover, we used quantitative reports of leukotriene B
4 (LTB4 ) synthesis inhibition in response to niflumic acid exposure to predict drug efficacy using Sigmoid Emax model. Population pharmacokinetics profiles of morniflumate were described using a multi-absorption (5-sequential) two-compartment model, and analysis of inter-individual variability suggested that volume of distribution in peripheral compartment was correlated with body mass index (BMI). Model simulation results showed that individuals with lower BMI had higher plasma concentrations of morniflumate and niflumic acid, resulting in increased and sustained inhibition of LTB4 synthesis. Under steady-state conditions, average plasma concentrations of morniflumate and niflumic acid were 2.66–2.68 times higher in group with a BMI of 17.36 kg/m2 compared to the group with a BMI of 28.41 kg/m2 . Additionally, inhibition of LTB4 synthesis was 1.02 times higher in group with a BMI of 17.36 kg/m2 compared to group with a BMI of 28.41 kg/m2 , and the fluctuation was significantly reduced from 6.06 to 0.01%. These findings suggest that the concentration of active metabolite in plasma following morniflumate exposure was lower in the obese group compared to the normal group, thus potentially reducing the drug's efficacy. [ABSTRACT FROM AUTHOR]- Published
- 2024
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13. Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics.
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Jang, Ji-Hun, Jeong, Seung-Hyun, and Lee, Yong-Bok
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FEXOFENADINE ,PHARMACOKINETICS ,GENETIC polymorphisms ,ALLERGIES ,THERAPEUTICS - Abstract
Fexofenadine is useful in various allergic disease treatment. However, the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking. This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability. Polymorphisms of the organic-anion-transporting-polypeptide (OATP) 1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity. Therefore, modeling was performed using fexofenadine oral exposure data according to the OATP1B1- and 2B1-polymorphisms. OATP1B1 and 2B1 were identified as effective covariates of clearance (CL/F) and distribution volume (V/F)-CL/F, respectively, in fexofenadine pharmacokinetic variability. CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17- and 2.20-folds, respectively, depending on the OATP1B1 polymorphism. Among the individuals with different OATP2B1 polymorphisms, the CL/F and V/F differed by up to 1.73- and 2.00-folds, respectively. Ratio of the areas under the curves following single- and multiple-administrations, and the cumulative ratio were significantly different between OATP1B1- and 2B1-polymorphism groups. Based on quantitative prediction comparison through a model-based approach, OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability. Based on the established pharmacokinetic-pharmacodynamic relationship, the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25- and 0.87-times, respectively, and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well. This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine. [Display omitted] • OATP1B1 and 2B1 are effective covariates for fexofenadine pharmacokinetic diversity. • Fexofenadine systemic clearance is associated with the interplay of OATP1B1 and 2B1. • OATP1B1 polymorphism has a major effect on fexofenadine pharmacokinetics. • An approach to precision medicine for fexofenadine through pharmacometrics studies. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Population Pharmacokinetic Modeling of Zaltoprofen in Healthy Adults: Exploring the Dosage Regimen.
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Jang, Ji-Hun, Jeong, Seung-Hyun, and Lee, Yong-Bok
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PHARMACOKINETICS , *ADULTS , *GENETIC polymorphisms , *JUDGMENT (Psychology) , *INDIVIDUALIZED medicine - Abstract
Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Dosage exploration of meloxicam according to CYP2C9 genetic polymorphisms based on a population pharmacokinetic‐pharmacodynamic model.
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Jang, Ji‐Hun, Jeong, Seung‐Hyun, and Lee, Yong‐Bok
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GENETIC polymorphisms , *INHIBITION (Chemistry) , *INDIVIDUALIZED medicine , *PHARMACOKINETICS - Abstract
Background: Meloxicam, used for treating inflammatory diseases, shows large differences in metabolism according to CYP2C9 genetic polymorphisms; however, there are few studies on dose regimen setting based on quantitative predictions. Objective: The aim of this study was to determine the appropriate meloxicam dose regimen for each genotype through population pharmacokinetic‐pharmacodynamic modeling of meloxicam by considering CYP2C9 genetic polymorphisms. Methods: For modeling, previously reported pharmacokinetic (plasma concentration)‐pharmacodynamic (inhibition of thromboxane B2 generation) data of meloxicam were collected for CYP2C9 genetic polymorphisms (n = 43). And these data were mainly used in the modeling process. Through simulations of the established models, steady‐state pharmacokinetic‐pharmacodynamic profiles were obtained according to meloxicam multiple exposures for each CYP2C9 genotype, and predictions were made based on dose regimen changes. Results: Genetic polymorphisms of CYP2C9 were identified as key covariates that significantly affected pharmacokinetic variability of meloxicam between individuals. The developed meloxicam population pharmacokinetic‐pharmacodynamic model predicted pharmacokinetic results of the 7.5 mg meloxicam administration groups (n = 26) for CYP2C9*1/*1 and *1/*3 as an external validation. The results of model simulation revealed that the differences were 2.39–5.42 times for steady‐state mean plasma concentrations and 1.21–1.71 times for the degree of inhibition of thromboxane B2 generation following multiple exposures for CYP2C9*1/*1 versus *1/*13, *1/*3, and *3/*3. This suggested that thromboxane B2 inhibition following increased plasma exposure to meloxicam differed significantly according to CYP2C9 genetic polymorphisms. The dose of meloxicam in CYP2C9*1/*13, *1/*3, and *3/*3 was randomly adjusted to 1.6–15 mg to approximate the mean thromboxane B2 inhibition for CYP2C9*1/*1 at steady state, the dose intervals varied from 24 h to 48 h. Conclusions: The results suggested that clinical dose adjustment of meloxicam would be necessary to account for CYP2C9 genetic polymorphisms and reduce side effects. This study suggests a clearer direction for setting up clinical therapy based on personalized medicine and quantitative predictions for meloxicam. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Physiologically Based Pharmacokinetic (PBPK) Modeling of Lornoxicam: Exploration of doses for CYP2C9 Genotypes and Patients with Cirrhosis.
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Jeong, Seung-Hyun, Jang, Ji-Hun, and Lee, Yong-Bok
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CIRRHOSIS of the liver , *PHARMACOKINETICS , *GENOTYPES , *DRUG efficacy , *CLINICAL medicine - Abstract
Lornoxicam physiologically based pharmacokinetic (PBPK) models were developed and validated on the basis of clinical pharmacokinetic results obtained by considering CYP2C9 genetic polymorphisms in healthy adult populations. PBPK models were extended to predict lornoxicam pharmacokinetics for patients with cirrhosis by quantitatively examining the pathophysiological information associated with cirrhosis. The predicted plasma exposure to lornoxicam was approximately 1.12–2.83 times higher in the CYP2C9*1/*3 and *1/*13 groups than in the CYP2C9*1/*1 group of healthy adult populations and patients with cirrhosis. The predicted plasma exposure to lornoxicam was approximately 1.28–3.61 times higher in patients with cirrhosis than in healthy adult populations. If the relationship between lornoxicam exposure in plasma and drug efficacy was proportional, then the proposed adjusted doses of lornoxicam for each group varied from 1.25 mg to 8 mg. As the severity of cirrhosis increased, or when the CYP2C9 genotype was *1 heterozygous, the dose adjustment range of lornoxicam increased. Therefore, the effect of pathophysiological factors (cirrhosis severity) on the pharmacokinetics of lornoxicam might be more important than that of CYP2C9 genetic factors. These results could be useful for broadening the scope of clinical application of lornoxicam by enabling dose selection based on CYP2C9 genotypes and liver cirrhosis degree. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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17. Human risk assessment of 4-n-nonylphenol (4-n-NP) using physiologically based pharmacokinetic (PBPK) modeling: analysis of gender exposure differences and application to exposure analysis related to large exposure variability in population.
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, and Lee, Yong-Bok
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ENVIRONMENTAL exposure , *POISONS , *PHARMACOKINETICS - Abstract
As a toxic substance, 4-n-nonylphenol (4-n-NP) or 4-nonylphenol (4-NP) is widely present in the environment. 4-n-NP is a single substance with a linear-alkyl side chain, but 4-NP usually refers to a random mixture containing various branched types. Unfortunately, human risk assessment and/or exposure level analysis for 4-n-NP (or 4-NP) were almost nonexistent, and related research was urgently needed. This study aimed to analyze the various exposures of 4-n-NP (or 4-NP) through development of a physiologically based-pharmacokinetic (PBPK) model considering gender difference in pharmacokinetics of 4-n-NP and its application to human risk assessment studies. A PBPK model was newly developed considering gender differences in 4-n-NP pharmacokinetics and applied to a human risk assessment for each gender. Exposure analysis was performed using a PBPK model that considered gender differences in 4-n-NP (or 4-NP) exposure and high variabilities in several countries. Furthermore, an extended application was attempted as a human risk assessment for random mixture 4-NP, which is difficult to accurately evaluate in reality. External-exposure and margin-of-safety estimated with the same internal exposure amount differed between genders, meaning the need for a differentiated risk assessment considering gender. Exposure analysis based on biomonitoring data confirmed large variability in exposure to 4-n-NP (or 4-NP) by country, group, and period. External-exposures estimated using PBPK model varied widely, ranging from 0.039 to 63.875 mg/kg/day (for 4-n-NP or 4-NP). By country, 4-n-NP (or 4-NP) exposure was higher in females than in males and the margin-of-safety tended to be low. Overall, exposure to 4-n-NP (or 4-NP) in populations was largely not safe, suggesting need for ongoing management and monitoring. Considering low in vivo accumulation confirmed by PBPK model, risk reduction of 4-n-NP is possible by reducing its use. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms.
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, and Lee, Yong-Bok
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PHARMACOKINETICS , *DRUG therapy , *GENETIC polymorphisms , *MALES , *DRUG utilization , *PHENOTYPES - Abstract
Torsemide is a diuretic drug used for several cardiovascular and chronic diseases. With regard to the clinical application of torsemide, studies on individualized pharmacotherapy and modeling that take variability in pharmacokinetics (PKs) within a population into account have been rarely reported. Thus, the objective of this study was to perform population pharmacokinetic (Pop-PK) modeling and to identify effective covariates that could explain the inter-individual variability (IIV) of torsemide PK. Pop-PK modeling for torsemide was performed based on serum concentration data obtained from 112 healthy Korean males and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was fully verified. The model was also reconfirmed using NONMEM software. As a basic model, the PKs of torsemide within the population were well described by a two-compartment model reflecting the lag-time on oral absorption. According to the genetic polymorphisms of OATP1B1 and CYP2C9, significant associations were found in the V/F, CL/F, and CL2/F of torsemide. These were reflected as effective covariates in the final Pop-PK model of torsemide, resulting in an approximately 5–10% improvement in the model parameter IIV values. Considering that torsemide is a substrate for CYP2C9 and OATP1B1, it was important to search for genetic polymorphisms in CYP2C9 and OATP1B1 as covariates to explain the PK diversity of torsemide between individuals. The differences in CL/F and CL2/F between the phenotypes of CYP2C9 were approximately 36.5–51%. The difference in V/F between the phenotypes of OATP1B1 was approximately 41–64.6%. These results suggested that the phenotypes of CYP2C9 and OATP1B1 produced significant differences in torsemide PKs. Considering that CYP2C9 and OATP1B1 phenotypes as covariates affected different PK parameters of torsemide, it could be inferred that torsemide's cell membrane permeation process by OATP1B1 and the metabolic process by CYP2C9 could independently affect each other in vivo without interplay. There was no significant difference in the parameter estimates between modeling software (Phoenix NLME vs. NONMEM). In this study, the torsemide PK variability between individuals was largely explained. In the future, individualized effective drug therapy of torsemide taking individual patient's genotypes into account might become possible. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation.
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Lee, Jae Ha, Lee, Dong-Hwan, Kim, Jin Soo, Jung, Won-Beom, Heo, Woon, Kim, Yong Kyun, Kim, Se Hun, No, Tae-Hoon, Jo, Kyeong Min, Ko, Junghae, Lee, Ho Young, Jun, Kyung Ran, Choi, Hye Sook, Jang, Ji Hoon, and Jang, Hang-Jea
- Subjects
EXTRACORPOREAL membrane oxygenation ,MEROPENEM ,CRITICALLY ill ,PHARMACOKINETICS ,ADULTS ,MONTE Carlo method - Abstract
Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens. Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT
>MIC ), 100% fT>MIC , and 100% fT>4xMIC . Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50–130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC . However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC . Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed. [ABSTRACT FROM AUTHOR]- Published
- 2021
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20. Simultaneous determination of fourteen components of Gumiganghwal-tang tablet in human plasma by UPLC-ESI-MS/MS and its application to pharmacokinetic study.
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Jeong, Seung-Hyun, Jang, Ji-Hun, Lee, Guk-Yeo, Yang, Seung-Jung, Cho, Hea-Young, and Lee, Yong-Bok
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PHARMACOKINETICS ,FORMIC acid ,MASS spectrometers ,HERBAL medicine ,TRADITIONAL medicine - Abstract
Gumiganghwal-tang is a traditional herbal medicine widely used for its anti-inflammatory, analgesic, and antipyretic effects. However, the safety and efficacy of its active ingredients based on an in vivo pharmacokinetic (PK) study have yet been investigated. We have established a sensitive and accurate UPLC-ESI-MS/MS method and conducted a PK study on 14 constituents of Gumiganghwal-tang through human plasma analysis. Analytical conditions were optimized according to the physicochemical properties of the 14 compounds to facilitate efficient separation and eliminate overlap or interference between peaks. KINETEX-C 18 and Inertsil-C 8 columns were used as UPLC stationary phases, and acetonitrile and aqueous formic acid were used as mobile phases. All the analytes were quantified with a triple quadrupole mass spectrometer using electrospray ionization in multiple reaction monitoring mode. The chromatograms of 14 bioactive compounds showed excellent elution and sensitivity, and each peak was selectively separated and quantified without interference with each other or impurities. The established analytical method was based on international guidelines and was successfully used to perform PK studies of 14 herbal ingredients in humans after oral administration with Gumiganghwal-tang tablets. The oral absorption of most active components of Gumiganghwal-tang was relatively rapid and remained considerably long in the body to be quantified in plasma up to 48 h after administration. [Display omitted] • Establishment and validation of simultaneous analysis of Gumiganghwal-tang components. • Quantification of 14 major components of Gumiganghwal-tang from human plasma samples. • Exploring the pharmacokinetic characteristics of Gumiganghwal-tang tablet in humans. [ABSTRACT FROM AUTHOR]
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- 2021
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21. Human risk assessment of di-isobutyl phthalate through the application of a developed physiologically based pharmacokinetic model of di-isobutyl phthalate and its major metabolite mono-isobutyl phthalate.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, and Lee, Yong-Bok
- Subjects
- *
HEALTH risk assessment , *PHTHALATE esters , *PHARMACOKINETICS , *SUBSTANCE abuse , *RATS , *BIOMARKERS - Abstract
Di-isobutyl phthalate (DiBP) is a substance used in the production of objects frequently used in human life. Mono-isobutyl phthalate (MiBP), a major in vivo metabolite of DiBP, is a biomarker for DiBP exposure assessment. Therefore, risk assessment studies on DiBP and MiBP, which have not yet been reported in detail, are needed. The aim of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for DiBP and MiBP in rats and extend this to human risk assessment based on human exposure. Pharmacokinetic studies were performed in male rats following the administration of 5–100 mg/kg DiBP, and these results were used for the development and validation of the PBPK model. In addition, the previous pharmacokinetic results in female rats following DiBP administration and the pharmacokinetic results in both males and females according to multiple exposures to DiBP were used to develop and validate the PBPK model. The metabolism of DiBP to MiBP in the body was very significant and rapid, and the biodistribution of MiBP was broad and major. Furthermore, the amount of MiBP in the body showed a correlation with DiBP exposure, and from this, a PBPK model was developed to evaluate the external exposure of DiBP from the internal exposure of MiBP. The predicted rat plasma, urine, fecal, and tissue concentrations using the developed PBPK model fitted well with the observed values. The established PBPK model for rats was extrapolated to a human PBPK model of DiBP and MiBP based on human physiological parameters and allometric scaling. The reference dose of 0.512 mg/kg/day of DiBP and external doses of 6.14–280.90 μg/kg/day DiBP for human risk assessment were estimated using Korean biomonitoring values. Valuable insight and approaches to assessing human health risks associated with DiBP exposure were provided by this study. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
22. Pharmacokinetic comparison with different assays for simultaneous determination of cis-, trans-cefprozil diastereomers in human plasma.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, and Lee, Yong-Bok
- Subjects
DIASTEREOISOMERS ,PHARMACOKINETICS ,FORMIC acid ,ACETIC acid ,WATER use - Abstract
The purpose of this study was to compare pharmacokinetic (PK) parameters obtained using two newly developed assays, HPLC-UV and UPLC-ESI-MS/MS. Selection of assay and results obtained therefrom are very important in PK studies and can have a major impact on the PK-based clinical dose and usage settings. For this study, we developed two new methods that are most commonly used in biosample analysis and focused on PK parameters obtained from them. By HPLC-UV equipped with a Luna-C 8 column using UV detector, cefprozil diastereomers were separated using water containing 2% (V/V) acetic acid and acetonitrile as a mobile phase. By UPLC-ESI-MS/MS equipped with a HALO-C 18 column, cefprozil diastereomers were separated using 0.5% (V/V) aqueous formic acid containing 5 mM ammonium-formate buffer and methanol as a mobile phase. Chromatograms showed high resolution, sensitivity, and selectivity without interference by plasma constituents. Both intra- and inter-day precisions (CV, %) were within 8.88% for HPLC-UV and UPLC-ESI-MS/MS. Accuracy of both methods was 95.67%–107.50%. These two analytical methods satisfied the criteria of international guidance and could be successfully applied to PK study. Comparison of PK parameters between two assays confirmed that there is a difference in the predicted minimum plasma concentrations at steady state, which may affect clinical dose and usage settings. Furthermore, we confirmed possible correlation between PK parameters and various biochemical parameters after oral administration of 1000 mg cefprozil to humans. [Display omitted] • Development of UPLC-ESI-MS/MS and HPLC-UV methods for cefprozil diastereomers. • Comparison of PK parameters obtained using two newly developed assays. • Possible correlation between PK parameters and various biochemical parameters. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
23. Simultaneous determination of three iridoid glycosides of Rehmannia glutinosa in rat biological samples using a validated hydrophilic interaction–UHPLC–MS/MS method in pharmacokinetic and in vitro studies.
- Author
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Jeong, Seung‐Hyun, Jang, Ji‐Hun, Cho, Hea‐Young, and Lee, Yong‐Bok
- Subjects
- *
BIOAVAILABILITY , *TANDEM mass spectrometry , *HIGH performance liquid chromatography , *GRADIENT elution (Chromatography) , *PHARMACOKINETICS , *IN vitro studies - Abstract
The purpose of this study was to develop a method for simultaneous analysis of aucubin, catalpol, and geniposide, which are representative iridoid glycoside constituents of Rehmannia glutinosa, in rat plasma, urine, and feces using hydrophilic interaction ultra high‐performance liquid chromatography with tandem mass spectrometry. The three components were separated using 10 mmol/L aqueous ammonium formate containing 0.01% (v/v) formic acid and acetonitrile as a mobile phase by gradient elution at a flow rate of 0.2 mL/min, equipped with a Kinetex® HILIC column (50 × 2.1 mm, 2.6 μm). Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization and operated in multiple reaction monitoring mode. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma constituents. In all three iridoid glycosides, both the intra‐ and interbatch precisions (coefficient of variation %) were less than 4.81%. The accuracy was 96.56–103.55% for aucubin, 95.23–106.21% for catalpol, and 94.50–104.16% for geniposide. The developed analytical method satisfied the criteria of international guidance and was successfully applied to pharmacokinetic studies including oral bioavailability of aucubin, catalpol, and geniposide, and their urinary and fecal excretion ratios after oral or intravenous administration to rats. The new method was also applied to measure plasma protein binding ratios in vitro. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
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24. Simultaneous measurement of epinastine and its metabolite, 9,13b‐dehydroepinastine, in human plasma by a newly developed ultra‐performance liquid chromatography–tandem mass spectrometry and its application to pharmacokinetic studies.
- Author
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Jeong, Seung‐Hyun, Jang, Ji‐Hun, Cho, Hea‐Young, and Lee, Yong‐Bok
- Abstract
Epinastine is an antiallergic drug with high selectivity for histamine receptors. It has been reported that 9,13b‐dehydroepinastine is present as a metabolite in vivo in humans, but there was little information about their pharmacokinetics (PKs) in humans. Although several analytical methods have been reported for epinastine analysis in different matrices, none are available for its metabolite. Therefore, the purpose of this study was to develop an analytical method to simultaneously measure epinastine and its metabolite, 9,13b‐dehydroepinastine, in human plasma samples using an ultra‐performance liquid chromatography–tandem mass spectrometer. Analytes were separated on a C18 column. Quantification of this analysis was performed on a triple‐quadrupole mass spectrometer. Chromatograms showed high sensitivity, selectivity, and resolution with no interference with plasma constituents. Calibration curves for both epinastine and 9,13b‐dehydroepinastine in human plasma were 0.1–50 ng/ml and displayed excellent linearity with correlation coefficients (r2) >0.99. The developed analytical method satisfied the criteria of international guidance and was validated. The method could be successfully applied to pharmacokinetic studies of epinastine and, for the first time, the metabolite kinetics of epinastine to 9,13b‐dehydroepinastine in humans after oral administration of 20 mg epinastine hydrochloride tablets. Our study is expected to be useful in future studies such as dosage settings and clinical pharmacotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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25. Risk assessment for humans using physiologically based pharmacokinetic model of diethyl phthalate and its major metabolite, monoethyl phthalate.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, and Lee, Yong-Bok
- Subjects
- *
DIETHYL phthalate , *HEALTH risk assessment , *PHTHALATE esters , *PHARMACOKINETICS , *ENDOCRINE disruptors , *INTRAVENOUS therapy - Abstract
Diethyl phthalate (DEP) belongs to phthalates with short alkyl chains. It is a substance frequently used to make various products. Thus, humans are widely exposed to DEP from the surrounding environment such as food, soil, air, and water. As previously reported in many studies, DEP is an endocrine disruptor with reproductive toxicity. Monoethyl phthalate (MEP), a major metabolite of DEP in vivo, is a biomarker for DEP exposure assessment. It is also an endocrine disruptor with reproductive toxicity, similar to DEP. However, toxicokinetic studies on both MEP and DEP have not been reported in detail yet. Therefore, the objective of this study was to evaluate and develop physiologically based pharmacokinetic (PBPK) model for both DEP and MEP in rats and extend this to human risk assessment based on human exposure. This study was conducted in vivo after intravenous or oral administration of DEP into female (2 mg/kg dose) and male (0.1–10 mg/kg dose) rats. Biological samples consisted of urine, plasma, and 11 different tissues. These samples were analyzed using UPLC–ESI–MS/MS method. For DEP, the tissue to plasma partition coefficient was the highest in the kidney, followed by that in the liver. For MEP, the tissue to plasma partition coefficient was the highest in the liver. It was less than unity in all other tissues. Plasma, urine, and fecal samples were also obtained after IV administration of MEP (10 mg/kg dose) to male rats. All results were reflected in a model developed in this study, including in vivo conversion from DEP to MEP. Predicted concentrations of DEP and MEP in rat urine, plasma, and tissue samples using the developed PBPK model fitted well with observed values. We then extrapolated the PBPK model in rats to a human PBPK model of DEP and MEP based on human physiological parameters. Reference dose of 0.63 mg/kg/day (or 0.18 mg/kg/day) for DEP and external doses of 0.246 μg/kg/day (pregnant), 0.193 μg/kg/day (fetus), 1.005–1.253 μg/kg/day (adults), 0.356–0.376 μg/kg/day (adolescents), and 0.595–0.603 μg/kg/day (children) for DEP for human risk assessment were estimated using Korean biomonitoring values. Our study provides valuable insight into human health risk assessment regarding DEP exposure. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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26. P-glycoprotein mechanical functional analysis using in silico molecular modeling: Pharmacokinetic variability according to ABCB1 c.2677G > T/A genetic polymorphisms.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, and Lee, Yong-Bok
- Subjects
- *
GENETIC polymorphisms , *FUNCTIONAL analysis , *PHARMACOKINETICS , *STRUCTURAL models , *FEXOFENADINE , *PROTEIN-ligand interactions - Abstract
P-glycoprotein (P-gp) is a widely membrane-expressed multi-drug transporter. It is unclear whether the pharmacokinetic diversity of P-gp substrates is highly dependent on ABCB1 polymorphisms encoding P-gp. The purpose of this study is to analyze the mechanistic function of P-gp through in silico molecular modeling and to approach the resolution of controversy over pharmacokinetic differences according to ABCB1 polymorphisms. P-gp conformations of apo, ligand-docked, and outward-facing states can be modeled based on structural information of human P-gp. And polymorphic P-gp structures were constructed through homology modeling. ABCB1 c.2677G > T/A (Ala893Ser/Thr), did not correspond to P-gp's nucleotide-binding-domain (NBD) or drug-binding-pocket (DBP) or involve mechanical conformational changes. Although amino acid substitution by ABCB1 c.2677G > T/A caused a 30 % increased strain in an α -helix hinge between the NBD and DBP in P-gp's internal tunnel, there were no overall structural changes compared to wild-type. ABCB1 c.2677G > T/A may increase torsional energy, impacting conformational change rate, but this does not significantly affect P-gp's general functioning. Fexofenadine docking into P-gp's DBP explained the substrate interaction, but no effect by ABCB1 c.2677G > T/A was confirmed. Our findings provide additional insights useful in resolving the debate about the influence of ABCB1 polymorphisms on the interindividual pharmacokinetic variability of P-gp substrates. • A structure-based mechanism of P-glycoprotein (P-gp) through molecular modeling • ABCB1 c.2677G > T/A gene polymorphism was not major for functional changes in P-gp. • Ala893Ser/Thr is unlikely to be related to substrate pharmacokinetic variability. • Resolving the current the P-gp genetic polymorphism controversy • 3 steps for pharmacokinetic variability molecular anlaysis of P-gp substrates [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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27. Intraoperative administration of dexmedetomidine reduced the postoperative catheter-related bladder discomfort and pain in patients undergoing lumbar microdiscectomy.
- Author
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Kwon, Youngsuk, Jang, Ji Su, Hwang, Sung Mi, Lee, Jae Jun, and Tark, Hyonjin
- Subjects
- *
POSTOPERATIVE care , *CATHETER-associated urinary tract infections , *SPINAL anesthesia , *DEXMEDETOMIDINE , *PHARMACOLOGY , *PHARMACOKINETICS - Abstract
Purpose: We aimed to evaluate the effect of the intraoperative dexmedetomidine (DEX) on the incidence and severity of catheter-related bladder discomfort (CRBD) after non-urologic surgery. The secondary aim was to find the correlation between the levels of CRBD and postoperative pain sensation.Methods: Adult male patients undergoing lumbar microdiscectomy were enrolled. Patients were randomized into two groups. After propofol administration, group D (
n = 35) received DEX at a loading dose of 1 μg/kg over 10 min, followed by a continuous infusion of 0.3–0.5 μg/kg/h until the end of surgery. In group C (n = 35), an identical volume of 0.9% saline was infused in the same manner. Induction and maintenance of anesthesia were standardized. The incidence and severity of CRBD, postoperative pain, and adverse effects were assessed at 1, 3, and 6 h after surgery.Results: The incidence of CRBD was significantly lower in group D than in group C at 1 h (34.3 vs. 62.9%,P = 0.017), 3 h (25.7 vs. 60%,P = 0.004), and 6 h (17.1 vs. 54.3%.P = 0.001) postoperatively. The severity of CRBD at 1, 3, and 6 h postoperatively was less in group D than in group C. Postoperative pain score was significantly lower in group D than in group C at 3 and 6 h postoperatively. Adverse events were comparable between two groups. There was a significant correlation between the severity of CRBD and postoperative pain score.Conclusions: Intraoperative administration of DEX is a safe and effective practice for the prevention of CRBD after lumbar microdiscectomy and can reduce postoperative pain. [ABSTRACT FROM AUTHOR]- Published
- 2018
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28. Pharmacokinetic Comparison between Methotrexate-Loaded Nanoparticles and Nanoemulsions as Hard- and Soft-Type Nanoformulations: A Population Pharmacokinetic Modeling Approach.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, and Lee, Yong-Bok
- Subjects
- *
PHARMACOKINETICS , *NANOPARTICLES , *OLIVE oil - Abstract
The purpose of this study was to identify and explore the differences in pharmacokinetics between different nanoformulations. This was done by comparing the pharmacokinetics of methotrexate-loaded nanoparticles [poly(lactic-co-glycolic acid); size of 163.70 ± 10.25 nm] and nanoemulsions (olive oil and Labrasol; size of 173.77 ± 5.76 nm), which represent hard- and soft-type nanoformulations, respectively. In addition, the population pharmacokinetic modeling approach as a useful tool for the comparison of pharmacokinetics between nanoformulations was newly proposed through this study. Significant pharmacokinetic differences were identified between nanoformulations through the new population pharmacokinetic modeling approach. As a result, the formulation type was explored as a significant covariate. The clearance and bioavailability of methotrexate-loaded nanoemulsions tended to decrease by 99% and increase by 19%, respectively, compared to those of the nanoparticles. The exploration of significant pharmacokinetic differences between drug formulations and their correlations presented in this study provide new perspectives on the development of nanoformulations. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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29. Population Pharmacokinetic Analysis of Cefaclor in Healthy Korean Subjects.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, Lee, Yong-Bok, Han, Hyo-Kyung, and Lee, Beom-Jin
- Subjects
- *
PHARMACOKINETICS , *KOREANS , *BODY weight , *CEPHALOSPORINS - Abstract
The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor's final population pharmacokinetic model was validated and some of the population's pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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30. Pharmacokinetic Changes According to Single or Multiple Oral Administrations of Socheongryong-Tang to Rats: Presented as a Typical Example of Changes in the Pharmacokinetics Following Multiple Exposures to Herbal Medicines.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, Jung, Da-Hwa, Lee, Guk-Yeo, Lee, Yong-Bok, and Wasan, Kishor M.
- Subjects
- *
TANDEM mass spectrometry , *LIQUID chromatography-mass spectrometry , *HERBAL medicine , *CINNAMIC acid , *PHARMACOKINETICS - Abstract
The purpose of this study was to investigate the pharmacokinetic properties of ephedrine, paeoniflorin, and cinnamic acid after single or multiple doses of Socheongryong-tang (SCRT) were administered to rats, and to present an example of the pharmacokinetic changes following multiple doses of an herbal medicine. SCRT is a traditional herbal medicine that has been used clinically for a long time, and its main ingredients include ephedrine, paeoniflorin, and cinnamic acid. However, studies on the pharmacokinetic properties of SCRT are insufficient, and particularly, no pharmacokinetic information has been reported for multiple doses. In this study, SCRT was administered orally to rats once or multiple times, and plasma sampled at different times was quantitatively analyzed for ephedrine, paeoniflorin, and cinnamic acid using ultra-high-performance liquid chromatography-tandem mass spectrometry. There was a difference between the pharmacokinetic parameter values of each component (especially in paeoniflorin and cinnamic acid) obtained after single or multiple doses of SCRT. The actual observed values of each component obtained after multiple doses of SCRT were clearly different from the predicted results of multiple-dose simulations based on the pharmacokinetic profiles obtained after a single dose. The results confirmed that the plasma concentrations and, thus, exposures to paeoniflorin and cinnamic acid were significantly increased when SCRT was administered multiple times, whereas that of ephedrine was not. The results of this study are expected to provide useful pharmacokinetic data for the safety and efficacy evaluation of SCRT in the future and demonstrate the necessity of pharmacokinetic comparison studies according to single or multiple oral administrations of herbal medicines. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
31. In vivo and in vitro studies of Banhahoobak-tang tablets using UPLC-ESI-MS/MS with polarity switching.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, Lee, Guk-Yeo, Yang, Seung-Jung, Cho, Hea-Young, and Lee, Yong-Bok
- Subjects
- *
BLOOD proteins , *PROTEIN binding , *IN vitro studies , *IN vivo studies , *PHARMACEUTICAL services insurance , *HYDROCHLOROTHIAZIDE , *TANDEM mass spectrometry , *DRUG interactions - Abstract
• First report of clinical pharmacokinetic study of Banhahoobak-tang tablets. • First report of in vitro analysis for 18 main components of Banhahoobak-tang. • Provide scientific evidence for clinical use of Banhahoobak-tang. • Serve as a basis for designing dosage forms of Banhahoobak-tang tablets. • Useful for effectiveness, safety, and quality evaluation of Banhahoobak-tang tablets. Banhahoobak-tang is the most prescribed herbal drug in East Asia when individuals experience sudden symptoms such as sore throat or neurological symptoms. The low toxicity and high in-vivo safety of this herbal medicine has made it more attractive to patients, and it has recently been formulated as tablets. In addition, Banhahoobak-tang tablets are registered as health insurance drugs in South Korea, and clinical prescriptions and demand are increasing. However, there are very few clinical trial data as well as very little accurate content analysis and results for Banhahoobak-tang tablets. The purpose of this study was to perform in-vitro and in-vivo studies on Banhahoobak-tang tablets, including content analysis, pharmacokinetics in humans, and plasma protein binding. For this study, a UPLC-ESI-MS/MS method with polarity switching was developed for simultaneous analysis of 18 components of Banhahoobak-tang. To separate the analytes, a C 8 reverse-phase column was used as the stationary phase, 0.1 % aqueous formic acid and acetonitrile as the mobile phase, and ionization and multiple reaction monitoring for quantification. The developed method was able to isolate and quantify the 18 components with good sensitivity and selectivity and was fully validated according to international analytical standards. Stability tests were also conducted on the analytes. Finally, the method was applied to in-vitro and in-vivo studies of Banhahoobak-tang tablets, and the tablet components were 52.49 ng/g to 91.00 μg/g on average. The detected components showed rapid oral absorption in humans as well as high plasma protein binding ratio overall. These results and methods can be useful not only for effectiveness and safety evaluation but also for quality control of Banhahoobak-tang tablets. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
32. Enhanced Lymphatic Delivery of Methotrexate Using W/O/W Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study.
- Author
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Jang, Ji-Hun, Jeong, Seung-Hyun, and Lee, Yong-Bok
- Subjects
- *
PHARMACOKINETICS , *METHOTREXATE , *ZETA potential , *INTRAVENOUS therapy , *OLIVE oil , *HYDROXYTYROSOL , *SPRAYING & dusting in agriculture - Abstract
Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, −35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
33. Pharmacokinetic Comparison of Three Different Administration Routes for Topotecan Hydrochloride in Rats.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, and Lee, Yong-Bok
- Subjects
- *
DRUG administration , *PHARMACOKINETICS , *BIOAVAILABILITY , *TOPOTECAN , *INTRAVENOUS therapy , *RATS - Abstract
Topotecan is actively used in clinic, with its primary use being in treatment of various types of cancer. The approved administration routes are oral and intravenous. The purpose of this study was to investigate and identify pharmacokinetic profiles of different administration routes. We conducted pharmacokinetic studies on three different routes of administration in rats. Five rats in each group received a single dose of 4 mg/kg of topotecan hydrochloride intravenously, orally, or subcutaneously, and the concentrations of lactone and total forms of the drug in plasma, urine, and feces were quantified. Various pharmacokinetic parameters were compared statistically. Plasma concentrations of both the lactone and total forms at elimination phase following subcutaneous administration, were two times higher than was seen with oral administration and 10 times higher than with intravenous administration. Subcutaneous administration of topotecan showed pharmacokinetic profiles similar to sustained release. In addition, subcutaneous administration showed bioavailability from 88.05% (for lactone form) to 99.75% (for total form), and these values were four–five times greater than those of oral administration. The results of this non-clinical study will not only provide greater understanding of the in vivo pharmacokinetics of topotecan, but also be useful for development of additional formulations and/or administration routes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
34. Pharmacokinetic Comparison of Epinastine Using Developed Human Plasma Assays.
- Author
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Jeong, Seung-Hyun, Jang, Ji-Hun, Cho, Hea-Young, Lee, Yong-Bok, Yoon, In-Soo, and Cho, Hyun-Jong
- Subjects
- *
HUMAN beings - Abstract
The purpose of the study was to develop two new methods, HPLC-UV and UPLC-MS/MS, for quantifying epinastine in human plasma and to compare pharmacokinetic (PK) parameters obtained using them. Even in the same sample, there may be a difference in the quantitative value of drug depending on the assay, so that minor changes in PK parameter values may affect drug dose and usage settings. Therefore, selection and establishment of analytical methods are very important in PK studies of drugs, and a comparison of PK parameters according to analytical methods will be vital. For this study of PK parameter change, we newly developed two methods, HPLC-UV and UPLC-MS/MS, which are most commonly used to quantify epinastine concentrations in human plasma. All developed methods satisfied the international guidelines and criteria for successful application to PK study of 20 mg epinastine hydrochloride tablets after oral administration to twenty-six humans. A comparison of these two methods for in vivo analysis of epinastine was performed for the first time. This comparison study confirmed that different dose and usage settings might be possible based on PK parameters calculated using other analyses. Such changes in calculated PK parameters according to analytical methods would be crucial in the clinic. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
35. Population Pharmacokinetics of Cis-, Trans-, and Total Cefprozil in Healthy Male Koreans.
- Author
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Jang, Ji-Hun, Jeong, Seung-Hyun, Cho, Hea-Young, and Lee, Yong-Bok
- Subjects
- *
PHARMACOKINETICS , *KOREANS , *ANTIBIOTICS , *CREATININE , *CEPHALOSPORINS , *MALES - Abstract
Cefprozil, one of cephalosporin antibiotics, has been used extensively in clinics. However, pharmacokinetic (PK) information on cefprozil is still very limited. There have been no reports of population pharmacokinetics (PPKs). A PPK model for cefprozil will be a great advantage for clinical use. Thus, the aim of this study was to develop a PPK model for cefprozil for healthy male Koreans. Clinical PK and demographic data of healthy Korean males receiving cefprozil at a dose of 1000 mg were analyzed using Phoenix® NLME™. A one-compartment model with first-order absorption with lag-time was constructed as a base model. The model was extended to include covariates that influenced between-subject variability. Creatinine clearance significantly influenced systemic clearance of cefprozil. The final PPK model for cis-, trans-, and total cefprozil was established and validated. PPK parameter values of cis- and total cefprozil were similar to each other, but different from those of trans-isomer. Herein, we describe the establishment of accurate PPK models of cis-, trans-, and total cefprozil for healthy male Koreans for the first time. It may be useful as a dosing algorithm for the general population. These results might also contribute to the development of stereoisomeric cefprozil. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
36. A novel and sensitive UPLC–MS/MS method to determine mequitazine in rat plasma and urine: Validation and its application to pharmacokinetic studies.
- Author
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Jeong, Seung‐Hyun, Jang, Ji‐Hun, and Lee, Yong‐Bok
- Abstract
The aim of this study was to develop an analytical method to determine mequitazine in rat plasma and urine. Mequitazine was separated by UPLC–MS/MS equipped with a Kinetex core–shell C18 column (50 × 2.1 mm, 1.7 μm) using 0.1% (v/v) aqueous formic acid and acetonitrile containing 0.1% (v/v) formic acid as a mobile phase by gradient elution at a flow rate of 0.3 mL/min. Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique operating in multiple reaction monitoring positive ion mode. Mass transitions were m/z 323.3 → 83.1 for mequitazine and 281.3 → 86.3 for imipramine as internal standard. Liquid–liquid extraction with ethyl acetate and protein precipitation with methanol were used for sample extraction. Chromatograms showed that the method had high resolution, sensitivity and selectivity without interference from plasma constituents. Calibration curves for mequitazine in rat plasma and urine were 0.02–200 ng/mL, showing excellent linearity with correlation coefficients (r2) >0.99. Both intra‐ and inter‐day precisions (CV%) were within 4.08% for rat plasma and urine. The accuracies were 99.58–102.03%. The developed analytical method satisfied the criteria of international guidance. It could be successfully applied to pharmacokinetic studies of mequitazine after oral and intravenous administration to rats. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
37. Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: Contribution of intestinal first-pass effect to low bioavailability in rats
- Author
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Chung, Hye J., Choi, Young H., Choi, Hye D., Jang, Ji M., Shim, Hyun J., Yoo, Moohi, Kwon, Jong W., and Lee, Myung G.
- Subjects
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PHARMACOKINETICS , *CHEMICAL kinetics , *INFLAMMATORY bowel diseases , *RATS - Abstract
Abstract: The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC0–∞ values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Clr values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC0–12h values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC0–24h of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
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