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Plateau is characterized by low oxygen, low pressure, strong radiation, cold and dryness, among which low oxygen is the main factor that affects the normal life activities of human body. Altitude hypoxia leads to significant changes in the metabolic characteristics of drugs in vivo, which in turn affects the efficacy and adverse actions of drugs. This paper summarizes the present situation of rational drug use in plateau area and pinpoints the existing problems. Meanwhile, we posit the strategies and measures for realizing rational and precise pharmacotherapy of plateau residents. First, we need to acquire a panoramic view of differential and relative pharmacokinetics and pharmacodynamics in between plateau area and plain area by carrying out comparative studies on drug metabolisms and on comprehensive drug efficacies and mechanisms. Second, we must apply the findings from basic research to clinical practice and formulate guidelines and recommendations of drug use for plateau habitants. Finally, we should eventually achieve precise and individualized drug use for plateau habitants based on their characteristic etiology and pathogenesis. [ABSTRACT FROM AUTHOR]

1. In clinical practice, diammonium glycyrrhizinate is usually used with omeprazole in patients with viral hepatitis and cirrhosis accompanied by peptic ulcers. However, the drug interaction between diammonium glycyrrhizinate and omeprazole remains unclear. 2. In this study, the effects of diammonium glycyrrhizinate on the pharmacokinetics of omeprazole was investigated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method. Male Sprague–Dawley rats were randomly assigned to two groups: omeprazole and omeprazole + diammonium glycyrrhizinate, and the main pharmacokinetic parameters were estimated after oral administration. It was found that using the omeprazole along with the diammonium glycyrrhizinate increased the AUC, AUMC, Cmax for omeprazole. 3. For this reason, we used the LC-MS/MS to detect the binding rate of plasma protein (BRPP) of omeprazole in rats, it was found that diammonium glycyrrhizinate could decrease the BRPP in rats. In addition, we found that diammonium glycyrrhizinate specifically inhibited the enzyme activity of the CYP2C19 and CYP3A4, which are involved in the metabolism of the omeprazole. 4. These results mean that diammonium glycyrrhizinate could inhibit the metabolism and increase the plasma concentration of the omeprazole in rats. Overall, diammonium glycyrrhizinate can influence the pharmacokinetics of omeprazole by inhibiting CYP2C19 and CYP3A4 activities and decreasing BRPP of omeprazole. [ABSTRACT FROM AUTHOR]

Context: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic. Objective: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism. Materials and methods: The pharmacokinetics of AC (1 mg/kg) with or without pretreatment of DST (100 mg/kg) were investigated using LC-MS/MS. The effects of DST (50 μg/mL) on the metabolic stability of AC were also investigated using rat liver microsome incubation systems. Results: The results indicated that Cmax (23.87 ± 4.27 vs. 38.94 ± 5.32 ng/mL), AUC(0-t) (41.01 ± 11.32 vs. 77.28 ± 12.92 ng h/mL), and t1/2 (1.91 ± 0.18 vs. 2.74 ± 0.23 h) decreased significantly (p < 0.05) when DST and AC were co-administered, which suggested that DST might influence the pharmacokinetic behavior of AC when they are co-administered. The metabolic stability (t1/2) of AC was also decreased (25.7 ± 5.2 vs. 42.5 ± 6.1) with the pretreatment of DST. Discussion and conclusions: This study indicated that the main components in DST could accelerate the metabolism of AC in rat liver microsomes and change the pharmacokinetic behaviors of AC. So these results showed that the herb-drug interaction between DST and AC might occur when they were co-administered. Therefore, the clinical dose of AC should be adjusted when DST and AC are co-administered. [ABSTRACT FROM AUTHOR]

Background This study was to investigate the influence of physiological changes and the expression of MRP2 efflux transporter on the pharmacokinetics of norfloxacin after acute exposure to high altitude 4300 m. Methods and Results The rats were randomly divided into high altitude group and plain group. Blood gas and biochemical analysis showed that the physiological parameters significantly changed at high altitude. The mRNA and protein expression of MRP2 in high altitude group were higher than plain group in rat small intestine and kidney, while was reduced in rat liver. The AUC, K a and C max of norfloxacin were significantly reduced in high altitude group (p < 0.05). However, the MRT, CL, t 1/2 and Vd were significantly increased (p < 0.05). Conclusions These results indicate that physiological indicators and expression levels of drug transporters MRP2 are changed in responded to high altitude, to severely affect norfloxacin pharmacokinetics. These changes may provide basis and new ideas to adjust the dosage and administration, so as to promote rational drug use in the high altitude. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended-release (XR) formulation has been designed to provide a once-daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice-daily immediate-release (IR) formulation. We conducted 2 randomized, open-label, phase 1 studies in healthy volunteers. Study A characterized single-dose and steady-state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single-dose and steady-state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high-fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half-life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) after single- and multiple-dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. [ABSTRACT FROM AUTHOR]

Losartan (LST) is a common chemical drug used to treat high blood pressure and reduce the risk of stroke in certain people with heart disease. Danshen, prepared from the dried root and rhizome of Salvia miltiorrhiza Bunge , has been widely used for prevention and treatment of various cardiovascular and cerebrovascular diseases. There are more than 35 formulations containing Danshen indexed in the 2010 Chinese Pharmacopoeia, which are often combined with LST to treat cardiovascular and cerebrovascular diseases in the clinic. The effects of the two major components of Danshen, salvianolic acid B (SA-B) and tanshinone IIA (Tan IIA), on the pharmacokinetics of losartan and its metabolite, EXP3174, in rats were investigated by liquid chromatography coupled with mass spectrometry (LC–MS). Male Sprague-Dawley rats were randomly assigned to 3 groups: LST, LST+SA-B and LST+Tan IIA, and the main pharmacokinetic parameters were estimated after oral administration of LST, LST+SA-B and LST+Tan IIA. It was found that there are significant differences in the pharmacokinetic parameters among the three groups: C max , t 1/2 , AUC , AUMC in the LST+SA-B group was smaller than those in group LST, while larger in group LST+Tan IIA. Further, the effects of SA-B and Tan IIA on the metabolism of losartan was also investigated using rat liver microsomes in vitro . The results indicated that SA-B can induce the metabolism of LST, while Tan IIA can inhibit the metabolism of LST in rat liver microsomes in vitro by regulating activities of CYP450 enzymes. In addition, the effect of SA-B and Tan IIA on CYP3A4 and CYP2C9 expression was studied in Chang liver cells by western-blotting and Real-time PCR. It was concluded that the two components of Danshen, SA-B and Tan IIA have different influences on the metabolism of LST: SA-B can obviously speed up the metabolism of LST by inducing CYP3A4/CYP2C9 activities and expression, however, Tan IIA can slow down the metabolism of LST by inhibiting CYP3A4/CYP2C9 activities. [ABSTRACT FROM AUTHOR]

Targeting and visualization of human telomerase reverse transcriptase (hTERT) represents a promising approach for providing diagnostic value. The uptake kinetics and imaging results of 99mTc-hTERT antisense oligonucleotides (ASON) in hTERT-expressing cells were examined in vitro and in vivo. The pharmacokinetics and acute toxicity studies of 99mTc-hTERT ASON were also performed. The labeling efficiencies of radiolabeled oligonucleotide reached 76 ± 5%, the specific activity was up to 1850 kBq/µg, and the radiochemical purity was above 96%. Radioactivity accumulated to a higher concentration in hTERT-expressing cells with antisense probe than with sense control ( p < 0.05). Lipid carrier incorporation significantly increased the transmembrane delivery of radiolabeled probes ( p < 0.05). hTERT-expressing xenografts in nude mice were clearly visualized at 6 h postinjection of the antisense probe but not the sense control probe. However, liposome did not increase the radioactivity accumulation of probes in tumors for either antisense or sense probe ( p > 0.05). Radioactivity counts per minute versus time profiles for 99mTc-hTERT ASON were biphasic, indicative of a three-compartment model. The pharmacokinetics parameters of half-life of distribution ( T1/2 α), half-life of elimination ( T1/2 β), total apparent volume of distribution (Vd), and total rate of clearance were 2.04 ± 0.48 min, 24 ± 4.8 min, 109.83 ± 17.20 mL, and 3.19 ± 0.17 mL/min, respectively. The acute toxicity study results showed the safe application of 99mTc-hTERT ASON in vivo. This study provides further evidences that 99mTc-hTERT ASON should be developed as a safe, potential molecular image-guided diagnostic agent. [ABSTRACT FROM AUTHOR]

Abstract: Background: Lersivirine is a next-generation non-nucleoside reverse transcriptase inhibitor under development for the treatment of HIV-1 infection. HIV-1-infected patients receiving methadone may have a limited choice of antiretroviral agents due to drug–drug interactions. As methadone is metabolized by CYP3A4 and lersivirine is a weak CYP3A4 inducer, it is possible that lersivirine may decrease methadone concentrations. This study evaluated the effect of lersivirine on the pharmacokinetics (PK) of R- and S-methadone enantiomers. Methods: An open-label, single-sequence study was performed in 13 HIV-negative volunteers receiving stable methadone maintenance therapy (MMT) (50–150mg QD) for ≥3 months. Healthy volunteers received their methadone to steady-state on Day 1 and lersivirine (1000mg QD) plus their same methadone dose on Days 2–11. Assessments included PK, safety, Short Opiate Withdrawal Scale (SOWS), Desires for Drugs Questionnaire (DDQ) and pupillary diameter measurements (PDMs). Results: Following administration of methadone alone or in combination with lersivirine, R- and S-methadone concentrations did not appear different (ratios of adjusted geometric means for PK parameters: 95–104%). Following co-administration of lersivirine and methadone, adverse events (AEs) were generally mild to moderate in severity. One patient discontinued due to nausea. An examination of objective (vital signs, AEs, PDM), subjective (SOWS and DDQ scores) and PK data suggested that subjects did not experience opioid withdrawal during the study. Conclusions: Co-administration of lersivirine (1000mg QD) with methadone did not result in clinically relevant changes in R-/S-methadone concentrations or opioid withdrawal symptoms. No methadone dose adjustment is required when lersivirine is administered alongside MMT. [Copyright &y& Elsevier]

DAPB, a new molecule including danshensu, borneol, and a mother nucleus of ACEI (Angiotensin-converting enzyme inhibitors), is being developed as an antihypertensive candidate compound. A rapid, accurate, and sensitive ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was established and validated for the determination of DAPB in rat plasma. Chromatographic separation was performed on an Agilent SB-C18 column after protein precipitation by acetonitrile with a mobile phase consisting of acetonitrile and deionized water with 0.02% formic acid and 5 mM NH4F (v/v) at a flow rate of 0.2 mL/min. Quantification was performed using electrospray positive ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The method was linear over the range of 2–1000 ng/mL. The intra- and inter-day precision was within 12%, with accuracies less than 7%. Stability was within the acceptable limits under various storage and processing conditions. No apparent matrix effect was detected. The validated method was applied to the pre-clinical pharmacokinetic study of DAPB after oral administration of 30 mg/kg and intravenous administration of 6 mg/kg in rats. [ABSTRACT FROM AUTHOR]

Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs. [ABSTRACT FROM AUTHOR]

Some newest studies indicated that drug transports may play the key role in pharmacokinetics changes under hypoxia at high altitude; MDR1 is now known to affect the disposition of many administered drugs and make a major contribution to absorption, distribution, metabolism, excretion. Different expression of MDR1 is frequently found in different normal tissues and tumor cells; it is important to better understand how MDR1 is regulated under hypoxia, which seems to be a complex and highly controlled process. Several signaling pathways and transcription factors have been described as being involved in the regulation of MDR1 expression, such as MAPK/ERK, nuclear factor-kappaB, hypoxia-inducible factor-1a, pregnane × receptor, constitutive androstane receptor and microRNA. Recently, researches have been increasingly appreciating long non-coding RNAs (lncRNAs) as an integral component of gene regulatory networks. lncRNAs play crucial roles in various biological processes ranging from epigenetic gene regulation, transcriptional control, post-transcriptional regulation, pre-mRNA processing and nuclear organization. A last recent research showed that H19 gene non-coding RNA is believed to induce P-glycoprotein expression under hypoxia. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. WHAT THIS STUDY ADDS • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. AIMS To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. METHODS In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). RESULTS In vitro studies demonstrated low potential for CYP inhibition (I C50 estimates tofacitinib >30 µ m), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥25 µ m) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration ( Cmax) (95.98, 108.87) was also wholly within this acceptance region. CONCLUSIONS These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole. [ABSTRACT FROM AUTHOR]

Nifedipine is completely absorbed by the gastrointestinal tract and its pharmacokinetics and metabolism may be influenced by microorganisms. If gut microbes are involved in the metabolism of nifedipine, plateau hypoxia may regulate the bioavailability and the therapeutic effect of nifedipine by altering the metabolic activity of the gut microbiota. We herein demonstrated for the first time that gut flora is involved in the metabolism of nifedipine by in vitro experiments. In addition, based on the results of 16S rRNA analysis of feces in rats after acute plateau, we first confirmed that the plateau environment could cause changes in the number and composition of intestinal microbes. More importantly, these changes in flora could lead to a slower metabolic activity of nifedipine in the body after an acute plateau, resulting in increased bioavailability and therapeutic efficacy of nifedipine. Our research will provide basis and new ideas for changes in the fecal flora of human acutely entering the plateau, and contribute to rational drug use of nifedipine. [ABSTRACT FROM AUTHOR]

Abstract: With studies indicative of altered renal excretion under high altitude‐induced hypobaric hypoxia, the consideration of better therapeutic approaches has long been the aim of research on the management of high altitude related illness. The pharmacokinetics of drugs such as furosemide might be altered under hypoxic conditions, making it essential to establish different dose‐regimens to maintain therapeutic efficacy or to avoid toxic side effects at high altitude. Simultaneously, drug–drug interactions (DDIs) mediated by OAT1 occur at high altitude, severely affecting furosemide pharmacokinetics. This study investigated the influence of acute exposure to high altitude at 4300 m on the renal excretion of furosemide in rats. Significant changes in physiological parameters and kidney histopathology were found after acute high altitude exposure. Compared with low altitude, the pharmacokinetics of furosemide and the expression level of OAT1 in kidney were significantly changed after rapid ascent to high altitude. Additionally, the down‐regulated OAT1 expression further sustained the potential mechanism for the decreased renal excretion of furosemide, resulting in extended residence of the drug in the human body. The elevation of AUC, Cmax, MRT, t1/2 of furosemide, and decreased CL at high altitude further reinforced the current findings. Moreover, the absorption of furosemide was markedly increased and renal excretion significantly declined after co‐administration of captopril, resulting in local drug interaction at high altitude. In conclusion, acute exposure to high altitude may significantly affect the renal excretion of furosemide and the pharmacokinetic parameters of furosemide were altered after co‐administration of captopril, which may then impact the conventional therapeutic dosage. [ABSTRACT FROM AUTHOR]

Ginseng polysaccharide (GP) is one of the most abundant components in Panax ginseng. However, the absorption pathways and mechanisms of GPs have not been investigated systematically due to the challenges of their detection. The fluorescein isothiocyanate derivative (FITC) was employed to label GP and ginseng acidic polysaccharide (GAP) to obtain target samples. HPLC-MS/MS assay was used to determine the pharmacokinetics of GP and GAP in rats. The Caco-2 cell model was used to investigate the uptake and transport mechanisms of GP and GAP in rats. Our results demonstrated that the absorption of GAP was more than that of GP in rats after gavage administration, while there was no significant difference between both after intravenous administration. In addition, we found that GAP and GP were more distributed in the kidney, liver and genitalia, suggesting that GAP and GP are highly targeted to the liver, kidney and genitalia. Importantly, we explored the uptake mechanism of GAP and GP. GAP and GP are endocytosed into the cell via lattice proteins or niche proteins. Both are transported lysosomally mediated to the endoplasmic reticulum (ER) and then enter the nucleus through the ER, thus completing the process of intracellular uptake and transportation. Our results confirm that the uptake of GPs by small intestinal epithelial cells is primarily mediated via lattice proteins and the cytosolic cellar. The discovery of important pharmacokinetic properties and the uncovering of the absorption mechanism provide a research rationale for the research of GP formulation and clinical promotion. [Display omitted] [ABSTRACT FROM AUTHOR]

Nifedipine is completely absorbed by the gastrointestinal tract and its pharmacokinetics and metabolism may be influenced by microorganisms. If gut microbes are involved in the metabolism of nifedipine, plateau hypoxia may regulate the bioavailability and the therapeutic effect of nifedipine by altering the metabolic activity of the gut microbiota. We herein demonstrated for the first time that gut flora is involved in the metabolism of nifedipine by in vitro experiments. In addition, based on the results of 16S rRNA analysis of feces in rats after acute plateau, we first confirmed that the plateau environment could cause changes in the number and composition of intestinal microbes. More importantly, these changes in flora could lead to a slower metabolic activity of nifedipine in the body after an acute plateau, resulting in increased bioavailability and therapeutic efficacy of nifedipine. Our research will provide basis and new ideas for changes in the fecal flora of human acutely entering the plateau, and contribute to rational drug use of nifedipine. [ABSTRACT FROM AUTHOR]

Background and Objectives: Crizotinib (250 mg twice daily) is the first anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small-cell lung cancer (NSCLC). The objectives of the current study were to evaluate the effects of mild, moderate, and severe renal impairment on crizotinib pharmacokinetics and to make crizotinib dosing recommendations for ALK-positive NSCLC patients with renal impairment on the basis of the findings. Methods: The effects of varying degrees of renal impairment on crizotinib pharmacokinetics were evaluated by: (1) analysis of mild and moderate renal impairment on multiple-dose pharmacokinetics of crizotinib in ALK-positive NSCLC patients from the PROFILE 1001 and PROFILE 1005 trials; (2) analysis of severe renal impairment on single-dose pharmacokinetics of crizotinib in volunteers (Study 1020); and (3) prediction of the effect of severe renal impairment on multiple-dose crizotinib pharmacokinetics using a physiologically-based pharmacokinetic model of crizotinib. Results: No clinically relevant changes in plasma crizotinib exposure were observed in NSCLC patients with mild or moderate renal impairment. After a single 250-mg dose, the area under the plasma concentration-time curve (AUC) for crizotinib was 1.8-fold greater in subjects with severe renal impairment than in those with normal renal function. Physiologically-based pharmacokinetic modeling indicated a similar increase in steady-state AUC after multiple dosing. Conclusions: These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250 mg once daily. [ABSTRACT FROM AUTHOR]

A sensitive and rapid ultra performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS) method was developed to determine dapoxetine and its two major metabolites (dapoxetine- N -oxide and desmethyldapoxetine) in human plasma simultaneously. After a simple protein precipitation, the analytes and the combined internal standard (carbamazepine) were separated on an Acquity UPLC BEH C18 column using a mobile phase of acetonitrile and 0.1% formic acid in water with gradient elution. Mass spectrometric analysis was performed using a XEVO TQD triple quadruple mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions are of m / z 306.3 → 261.2, m / z 322.2 → 261.2, m / z 292.2 → 261.2 and m / z 237.1 → 194.2 for dapoxetine, dapoxetine- N -oxide, desmethyldapoxetine and IS, respectively. The linearity of this method was found to be within the concentration range of 1.0–200 ng/mL for dapoxetine; 0.5–100 ng/mL for dapoxetine- N -oxide; and 0.1–5.0 ng/mL for desmethyldapoxetine in human plasma, respectively. Only 4.0 min was needed for an analytical run. Intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all of the concentrations. This assay was successfully used to support a clinical pharmacokinetic study following oral administration of dapoxetine tablets in healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

A specific, sensitive and high throughput ultra-high performance liquid chromatography–electrospray ionization tandem mass spectrometric method (UHPLC–ESI-MS/MS) was established and validated to assay geniposide (GE), a promising anti-inflammatory drug, in adjuvant arthritis rat plasma: application to pharmacokinetic and oral bioavailability studies and plasma protein binding ability. Plasma samples were processed by de-proteinised with ice-cold methanol and separated on an ACQUITY UPLC™ HSS C18 column (100 mm × 2.1 mm i.d., 1.8 μm particle size) at a gradient flow rate of 0.2 mL/min using acetonitrile–0.1% formic acid in water as mobile phase, and the total run time was 9 min. Mass detection was performed in selected reaction monitoring (SRM) mode with negative electro-spray ionization includes the addition of paeoniflorin (Pae) as an internal standard (IS). The mass transition ion-pair was followed as m / z 387.4 → 122.4 for GE and m / z 479.4 → 449.0 for IS. The calibration curves were linear over the concentration range of 2–50,000 ng/mL with lower limit of quantification of 2 ng/mL. The intra-day and inter-day precisions (RSD, %) of the assay were less than 8.4%, and the accuracy was within ±6.4% in terms of relative error (RE). Extraction recovery, matrix effect and stability were satisfactory in adjuvant arthritis rat plasma. The UHPLC–ESI-MS/MS method was successfully applied to a pharmacokinetic study of GE after oral administration of depurated GE at 33, 66, 132 mg/kg and intravenous injection at 33, 66, 132 mg/kg in adjuvant arthritis (AA) rats. In addition, it was found that GE has rapid absorption and elimination, low absolute bioavailability, high plasma protein binding ability in AA rats after oral administration within the tested dosage range. It suggested that GE showed slow distribution into the intra- and extracellular space, and the binding rate was not proportionally dependent on plasma concentration of GE when the concentration of GE was below 5.0 μg/mL. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration-time profile from time 0 to infinity (AUCinf) and maximum observed concentration (Cmax) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment-emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment. [ABSTRACT FROM AUTHOR]

Purpose: Benzalkonium chloride (BAK), a common preservative in eye drops, can induce ocular surface toxicity that may decrease glaucoma therapy compliance. The ocular hypotensive effect, pharmacokinetic (PK) profiles, and local tolerance of a preservative-free latanoprost 0.005% cationic emulsion (Catioprost®), and a BAK-preserved latanoprost 0.005% solution (Xalatan®), were compared. Methods: The ocular hypotensive effect was evaluated in monkeys with elevated intraocular pressure (IOP) induced by laser photocoagulation of the trabecular meshwork. Each monkey ( n=8) received both latanoprost formulations once daily for 5 consecutive treatment days in a crossover design with at least a 2-week washout period between treatments. IOP was measured at baseline (on day 1, no instillation), on vehicle treatment day (day 0), and on treatment days 1, 3, and 5 before drug instillation and then hourly for 6 h. In rabbits, the ocular and systemic concentrations of latanoprost free acid were determined following a single instillation and the local tolerance of twice daily instillations over 28 days was assessed. Results: Both the preservative-free and BAK-preserved latanoprost formulations shared the same efficacy profile with the maximum IOP reduction occurring 2 h after each morning dose (−15%, −20%, and −26%; −15%, −23%, and −23% on days 1, 3, and 5, respectively) and lasting through 24 h. The equivalence in efficacy was confirmed by the PK data demonstrating similar area under the curves (AUCs). While both formulations were well tolerated, the incidence of conjunctival hyperemia was reduced by 42% with the BAK-free latanoprost cationic emulsion. Conclusions: In animal models, a preservative-free latanoprost cationic emulsion was as effective as Xalatan® for lowering IOP with an improved ocular tolerance profile. [ABSTRACT FROM AUTHOR]

Abstract: A sensitive and reliable ultra-high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UHPLC–ESI–MS/MS) has been developed and validated for the simultaneous determination of three active components, i.e., tectorigenin, irigenin and irisflorentin, in rat plasma and urine after oral administration of Rhizoma Belamcandae extract. Chromatographic separation was achieved on a Zorbax SB-C18 column (50mm×2.1mm, 1.8μm; Agilent, USA) with gradient elution using a mobile phase that consisted of acetonitrile – 0.1% formic acid in water at a flow rate of 0.4mL/min. Detection was performed by a triple-quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode via polarity switching between the negative (for tectorigenin and irigenin) and positive (for irisflorentin) ionization modes. The calibration curve was linear over a range of 50–50,000ng/mL for tectorigenin, 10–5000ng/mL for irigenin and 0.1–200ng/mL for irisflorentin, respectively. The intra- and inter-day precisions (RSD %) were within 11.3% for all analytes, whereas the deviation of assay accuracies ranged from −8.7 to +11.1%. All analytes were proven to be stable during all sample storage and analysis procedures. This method was successfully applied to a pharmacokinetic study of the three isoflavones after oral administration of Rhizoma Belamcandae extract to rats. [Copyright &y& Elsevier]

• Data demonstrating the pharmacokinetics (PK), efficacy and tolerability of PF-734200, a potent DPP-IV inhibitor in subjects with normal renal function, have been published or presented. • This study provides better data on the PK of PF-734200 in subjects with varying degrees of renal insufficiency and in subjects with end-stage renal disease undergoing haemodialysis. In assessing the effects of renal impairment on the PK of PF-734200, this study provides evidence for potential dose adjustment of PF-734200 in patients with certain categories of renal impairment. PF-734200 is a potent, selective inhibitor of DPP-IV. This two-part study evaluated the pharmacokinetics (PK) of oral 20 mg PF-734200 in subjects with varying degrees of renal insufficiency or with end-stage renal disease (ESRD) requiring chronic haemodialysis (HD). The study also assessed the HD clearance of PF-734200 in ESRD. Part 1 included subjects with normal renal function or renal insufficiency but not on HD. Subjects received a single dose of 20 mg PF-734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1 h after HD, a single 20-mg dose was given to subjects with ESRD and serum samples were collected. After a 7-day washout, subjects received another dose followed by collection of serum samples (period 2), during which HD was initiated 4 h after dosing. Dialysate samples were collected to quantify amount of drug removed, from which HD clearance was calculated. The fraction of drug dialysed was calculated using an AUC-based method. Systemic exposures of PF-734200 increased approximately 1.5-, 2.2-, 2.1- and 2.8-fold in subjects with mild, moderate, or severe renal insufficiency or ESRD, respectively, compared with subjects with normal renal function. The terminal half-life increased from 16.2 h in subjects with normal renal function to 36.6 h in subjects with ESRD. Approximately, 29% of PF-734200 in the body after a single-dose administration was dialysed by 4 h HD. Systemic exposure of PF-734200 increases with decreasing renal function. The effect of HD on drug removal is modest. [ABSTRACT FROM AUTHOR]

Abstract: Flavanoid kaempferol is mainly present as glucuronides and sulfates in rat plasma, and small amounts of the intact aglycone are also detected. In the this study, a rapid, specific and sensitive liquid chromatography–electrospray ionization-tandem mass spectrometry method (HPLC–MS/MS) was developed and validated for determination of kaempferol and its major metabolite glucuronidated kaempferol in rat plasma. A liquid–liquid extraction with acetic ether was involved for the extraction of kaempferol and internal standard. Analytes were separated on a C18 column (150mm×2.1mm, 4.5μm, Waters Corp.) with isocratic elution at a flow-rate of 0.3mlmin−1. The mobile phase was consisted of 0.5% formic acid and acetonitrile (50:50, v/v). The Quattro Premier HPLC–MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique. The method was validated according to the FDA guidelines for validation of bioanalytical method. The validated method was successfully applied to the study of the pharmacokinetics in rats after oral administration of kaempferol with different doses. [Copyright &y& Elsevier]

A simple, rapid, sensitive column-switching HPLC method is described for the analysis of the 10-hydroxycamptothecin (HCPT) in human serum. A pre-column containing restricted access media (RAM) is used for the sample clean-up and trace enrichment and is combined with a C18 column for the final separation. The analytical time is 8 min. The HCPT is monitored with fluorescence detector, excitation and emission wavelengths being 385 and 539 nm, respectively. There is a linear response range of 1–1000 ng/ml with correlation coefficient of 0.998 while the limit of quantification is 0.1 ng/ml. The intra-day and inter-day variations are less than 5%. This analytic procedure has been applied to a pharmacokinetic study of HCPT in clinical patients and the pharmacokinetic parameters of one-compartment model are calculated. [Copyright &y& Elsevier]