Involvement of herb–herb interactions in the influences of Radix Scutellaria and Coptis Chinensis on the bioavailability of the anthraquinones form Rhei Rhizoma in rats
In this study, we aimed to determine the underlying mechanisms. The metabolisms of anthraquinones by intestinal flora were studied using rat fecal suspension (RFS); the metabolisms of rhein (a typical anthraquinone in DH) by rat intestine and liver were studied using rat intestine microsomes (RIMs) and rat liver microsomes (RLMs), respectively; the intestinal transport of rhein was studied using everted gut sacs. The results showed that HL decreased the amount of the free anthraquinones after incubation in RFS and inhibited the intestinal transport of rhein, but HQ antagonized the effect of HL. On the other hand, HQ strong...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Gender-dependent predictable pharmacokinetic method for tacrolimus exposure monitoring in kidney transplant patients
Abstract Tacrolimus (Tac) is an immunosuppressive drug with a narrow therapeutic width and highly variable pharmacokinetics. Therefore, monitoring of Tac blood concentrations is of utmost importance in the management of renal transplant recipients. The occurrence and intensity of adverse effects depend on blood concentration and total exposure of the organism to this drug. This implies finding a new gender-dependent predictable method for Tac exposure monitoring based on determination of the area under the time concentration curve (AUC). The primary aim of this study was to investigate gender differences in s...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Prediction of glucuronidated drug clearance in pediatrics (≤5 years): An allometric approach
Abstract Children are not small adults. The differences between children of different age groups and adults are not merely due to body weight, but also due to physiological and biochemical differences resulting in different rates of drug metabolism or renal clearance. Glucuronidation is an important pathway of drug metabolism. Therefore, the objective of this study is to evaluate the predictive performance of several allometric exponents in children of ≤5 years for the total clearance of drugs which are mainly metabolized by glucuronidation. Four exponents (0.75, 1.0, 1.2, or 1.4) on the body weights and ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics of omeprazole and its metabolites in three phases of menstrual cycle
Abstract Omeprazole (OMP) is effective in the treatment of gastric hyperacidity and is metabolized by CYP2C19 and CYP3A4. These enzymes are modulated by estrogen and progesterone which regulate the menstrual cycle. The variations in the pharmacokinetics (PK) of many drugs like amphetamine, benzodiazepines and caffeine have been reported during menstrual cycle. In present study, the PK of the omeprazole and its metabolites was investigated during various phases of the menstrual cycle. A single oral dose, open-label, non-controlled, pharmacokinetic study of omeprazole was conducted in healthy young/premenopausal fe...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Comparative pharmacokinetics of active alkaloids after oral administration of Rhizoma Coptidis extract and Wuji Wan formulas in rat using a UPLC–MS/MS method
Abstract Wuji Wan (WJW), containing Rhizoma Coptidis (Huanglian in Chinese, HL), Frutus Evodiae Rutaecarpae (Wuzhuyu, WZY) and Radix Paeoniae Alba (Baishao, BS), is a classical traditional Chinese medical formula employed in treating intestinal disorders. Berberine (BBR) and palmatine (PMT) are the major active alkaloids in HL and have analgesic and anti-microbial effects. A sensitive, specific and validated ultra-performance liquid chromatography–tandem mass spectrometric method was developed to investigate the pharmacokinetic profiles of BBR and PMT in rat plasma and in situ intestinal perfusion solution...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Changes of Absorptive and Secretory Transporting System of (1 → 3) β-D-glucan Based on Efflux Transporter in Indomethacin-induced Rat
ABSTRACT Infection and inflammation suppress the expression and activity of several drug transporters in liver. In the intestine, P-glycoprotein (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) are important barriers to the absorption of many clinically important drugs. The expression and activity of these proteins were examined under inflammation. Drug transport was determined in jejunum and ileum segments isolated from 1.0 mg/kg, 5.0 mg/kg, and 7.5 mg/kg indomethacin-treated or control rats in diffusion chambers. Transport of laminaran, us...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Effect of vitamin D on bioavailability and lipid lowering efficacy of simvastatin
Abstract The 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors known as “statins” are widely prescribed for the management of dyslipidemia. In spite of their muscle toxicity, use of statins has alarmingly increased worldwide. A recent report suggests that vitamin D (VD) levels are closely associated with lipid lowering activity and muscular toxicity of statins. However, data are limited and inconclusive. The present study was undertaken to investigate the effect of VD supplementation on the bioavailability and lipid lowering effect of simvastatin (ST). Adult Sprague–...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Metabolism of cisplatin in the organs of Rattus norvegicus : role of Glutathione S -transferase P1
Abstract Glutathione S-transferases (GSTs) play an important role in the biotransformation of endogenous compounds and xenobiotics as well as in the metabolic inactivation of pharmacologically active substances, including anticancer drugs. Using cisplatin as the prototype drug, we investigated if any correlation exists between GSH levels, GSTs/GSTP1 activity and the fate of cisplatin in different organs of Rattus norvegicus. GSH–cisplatin complex was prepared, purified by anion-exchange chromatography and subjected to mass spectroscopic analysis which confirmed the structure to be diglutathione-monoplat...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Michaelis–Menten elimination kinetics of etanercept, rheumatoid arthritis biologics, after intravenous and subcutaneous administration in rats
Abstract Etanercept was approved by the Food and Drug Administration (FDA) in 2010 as a biologic agent for the treatment of rheumatoid arthritis (RA). The aim of the study was to investigate the pharmacokinetic properties of etanercept after intravenous and subcutaneous injection in rats. The plasma concentration of etanercept was determined using an enzyme-linked immunosorbent assay (ELISA). Intravenous and subcutaneous administration of 2 mg/kg of etanercept to rats showed that etanercept was slowly absorbed (time to reach the peak drug concentration [T max] = 1.60 days, bioavailabi...
Source: European Journal of Drug Metabolism and Pharmacokinetics - March 1, 2015 Category: Drugs & Pharmacology Source Type: research

Pomegranate juice does not affect the disposition of simvastatin in healthy subjects
This study evaluated the effect of pomegranate juice on the disposition of simvastatin, a CYP3A4 substrate, and simvastatin acid, its active metabolite, compared with grapefruit juice in healthy subjects. A single oral pharmacokinetic study of 40 mg simvastatin was conducted as a three-way crossover (control, pomegranate, and grapefruit juices) in 12 healthy male subjects. The subjects took pomegranate or grapefruit juice three times per day for 3 days (900 mL/day) and on the third day, the pharmacokinetic study was executed. Blood samples were collected to 24 h post-dose and the pharmacokinetic paramet...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 27, 2015 Category: Drugs & Pharmacology Source Type: research

Impact of a high-cholesterol diet on expression levels of Niemann–Pick C1-like 1 and intestinal transporters in rats and mice
We examined the effects of an HC diet on their expression in small intestine and the differences between rats and mice in the responsive of this expression to an HC diet. In addition to these transporters, alterations in six representative drug and nutrient transporters (multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, sodium-glucose linked transporter, glucose transporter, and l-type amino acid transporter) and transcriptional factors such as hepatocyte nuclear factor (HNF)4α, sterol regulatory element-binding protein (SREBP)2, and liver X receptor (LXR)α were det...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 26, 2015 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic modeling of oxcarbazepine active metabolite in Chinese patients with epilepsy
Abstract The aim of the study was to develop a population pharmacokinetic (PPK) model of oxcarbazepine and optimize the treatment of oxcarbazepine in Chinese patients with epilepsy. A total of 108 oxcarbazepine therapeutic drug monitoring samples from 78 patients with epilepsy were collected in this study. The pharmacologically active metabolite 10,11-dihydro-10-hydrocarbamazepine (MHD) was used as the analytical target for monitoring therapy of oxcarbazepine. Patients’ clinical data were retrospectively collected. The PPK model for MHD was developed using Phoenix NLME 1.2 with a non-linear mixed-effect mode...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 21, 2015 Category: Drugs & Pharmacology Source Type: research

A study on the PK and BA profiles in the mouse body for leonurine O/O microemulsion with determination by the LC-MS/MS method
Abstract Leonurine (LE) has been found to have therapeutic efficacy in cerebral thrombosis, but its poor solubility in water leads to very low bioavailability. In this article, a leonurine O/O microemulsion (LE-ME) was prepared and investigated for its in vivo pharmacokinetic behavior and bioavailability in the mouse body using an aqueous suspension of leonurine (LE-SWW) for the control group. A simple, sensitive and specific method, HPLC-MS/MS, was developed for detection of the LE content in mouse plasma using n-benzoyl-l-arginine ethyl ester as an internal standard. The results demonstrated that the C ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 21, 2015 Category: Drugs & Pharmacology Source Type: research

Preparation, characterization and in vitro/vivo evaluation of tectorigenin solid dispersion with improved dissolution and bioavailability
Abstract The purpose of this study was to develop and evaluate a novel amorphous solid dispersion system for tectorigenin (TG). TG is one of isoflavone aglycones extracted from Iris tectorum and flowers of Pueraria thunbergiana, but its poor water solubility and low membrane permeability have severely restricted the clinical application. To increase the aqueous solubility and oral bioavailability of TG, we prepared the solid dispersions of tectorigenin (TG-SD) using a simple solvent evaporation process with TG, polyvinylpyrrolidone (PVP) and PEG4000 at weight ratio of 7:54:9 after tested in several ratios. The pre...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 10, 2015 Category: Drugs & Pharmacology Source Type: research

Physiologically based modeling of lisofylline pharmacokinetics following intravenous administration in mice
In conclusion, the mouse is a good model to study LSF pharmacokinetics following intravenous administration. The developed PBPK model may be useful to design future preclinical and clinical studies of this compound. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 8, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics of mycophenolate sodium co-administered with tacrolimus in the first year after renal transplantation
Abstract We assessed the relations between MPA, free MPA (fMPA) and MPA glucuronide (MPAG) pharmacokinetics and the clinical condition of renal transplant recipients treated with EC-MPS and tacrolimus (Tac) in the first post-transplant year. In 18 adult patients blood samples were collected up to 12 h after EC-MPS oral administration. EC-MPS metabolites’ plasma concentrations were determined using validated HPLC methods. All patients reached MPA area under the time–concentration curve (AUC0–12) above 30 µg h/mL. Most of the MPA, fMPA and all MPAG concentrations correlated sig...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 6, 2015 Category: Drugs & Pharmacology Source Type: research

Sunitinib tissue distribution changes after coadministration with ketoconazole in mice
Abstract Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50 mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30 min apart) of 60 mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib co...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 6, 2015 Category: Drugs & Pharmacology Source Type: research

Effects of dose, flow rate, and bile acid on diclofenac disposition in the perfused rat liver
This study indicated that the flow rate and bile acid in the perfused rat liver were key factors for bile flow rate and DF, DF-Glu, and DF-4′OH disposition in the absence of albumin. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 6, 2015 Category: Drugs & Pharmacology Source Type: research

Absorption, elimination and cerebrospinal fluid concentrations of nimodipine in healthy beagle dogs receiving human intravenous and oral formulation
Abstract Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 5, 2015 Category: Drugs & Pharmacology Source Type: research

Preparation, characterization and pharmacokinetics evaluation of clarithromycin-loaded Eudragit ® L-100 microspheres
Abstract The aim of this work was to prepare pH-dependent clarithromycin microsphere formulation by emulsion solvent evaporation method, employing Eudragit® L-100. Prepared microspheres were evaluated by carrying out in vitro release and in vivo pharmacokinetics studies. Drug–polymer interactions were studied by differential scanning calorimetry, X-ray diffractometry analyses and results showed that clarithromycin was molecularly dispersed in the polymer. The particle size distribution of microspheres was found over the range of 10~50 μm. The drug is hardly released in the HCl solution pH 1.2 in ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 5, 2015 Category: Drugs & Pharmacology Source Type: research

The CYP4502D6 *4 and *6 alleles are the molecular genetic markers for drug response: implications in colchicine non-responder FMF patients
Abstract The cytochrome P450 2D6 (CYP2D6) is a cytochrome P450 enzyme involved in the oxidative biotransformation of the xenobiotics, carcinogens and various clinically important drugs. Patients are evaluated in three sub-groups of extensive (EM), intermediate (IM) and poor metabolizer (PM) phenotypes due to their drug-metabolising ability for the target CYP2D6 gene. Colchicine non-responsive FMF patients were prospectively genotyped for the major CYP2D6 alleles in the current study. Major CYP2D6 alleles of *1, *3, *4, *5, and *6 were genotyped for 30 responsive and 60 non-responsive FMF patients by multiplex ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - February 2, 2015 Category: Drugs & Pharmacology Source Type: research

Physiologically based modeling of the pharmacokinetics of acetaminophen and its major metabolites in humans using a Bayesian population approach
Abstract The principal aim of this study was to develop, validate, and demonstrate a physiologically based pharmacokinetic (PBPK) model to predict and characterize the absorption, distribution, metabolism, and excretion of acetaminophen (APAP) in humans. A PBPK model was created that included pharmacologically and toxicologically relevant tissue compartments and incorporated mechanistic descriptions of the absorption and metabolism of APAP, such as gastric emptying time, cofactor kinetics, and transporter-mediated movement of conjugated metabolites in the liver. Through the use of a hierarchical Bayesian framework...
Source: European Journal of Drug Metabolism and Pharmacokinetics - January 31, 2015 Category: Drugs & Pharmacology Source Type: research

Comparison of pharmacokinetic and safety profiles between Bemfola ® and Gonal-f ® after subcutaneous application
The objective of this study was to show that Bemfola® yields comparable clinical pharmacokinetic (PK) and safety profiles to Gonal-f® in healthy female subjects. In this randomized, Phase I trial conducted in healthy female volunteers (N = 32), a 2-period, balanced 2-treatment crossover design was used. A single subcutaneous dose of 225 IU Bemfola® or Gonal-f® was administered in each treatment period per sequence. Blood was collected for pharmacokinetic analysis until 10 days after each r-hFSH treatment. For down-regulation of endogenous FSH subjects were given a depot injection with le...
Source: European Journal of Drug Metabolism and Pharmacokinetics - January 30, 2015 Category: Drugs & Pharmacology Source Type: research

Efflux and uptake transporters involved in the disposition of bazedoxifene
Abstract Bazedoxifene, a novel selective estrogen receptor modulator, has complex pharmacokinetics with rapid absorption, high metabolic clearance, low oral bioavailability (6.25 %) and a slow elimination phase. Our hypothesis is that drug uptake and efflux transporters may play an important role in its disposition. To adequately cover all aspects of bazedoxifene transport, several approaches were undertaken: PAMPA assay, ATPase assay, membrane inside-out vesicles and Caco-2 and CHO cell lines. The results obtained from PAMPA experiments showed moderate passive permeability of bazedoxifene (P app&nb...
Source: European Journal of Drug Metabolism and Pharmacokinetics - January 29, 2015 Category: Drugs & Pharmacology Source Type: research

A comparison of the pharmacokinetics of three different preparations of total flavones of Hippophae rhamnoides in beagle dogs after oral administration
Abstract Pharmacokinetic properties of isorhamnetin, quercetin, and kaempferol in three different total flavones of Hippophae rhamnoides (TFH) preparations were compared after oral administration to beagle dogs by a UPLC–MS method. The pharmacokinetic results showed that C max of isorhamnetin and quercetin in TFH solid dispersion (TFH-SD) and TFH self-emulsifying (TFH-SE) preparations was significantly enhanced than that in TFH preparations (p 
Source: European Journal of Drug Metabolism and Pharmacokinetics - January 23, 2015 Category: Drugs & Pharmacology Source Type: research

Effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats
Abstract The purpose of this study was to investigate the possible effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The effects of pioglitazone on P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 activities were also evaluated. Nifedipine was mainly metabolized by CYP3A4. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administrations of nifedipine to rats in the presence and absence of pioglitazone (0.3 and 1.0 mg/kg). Pioglitazone inhibited the CYP3A4 enzyme activity in a concent...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 30, 2014 Category: Drugs & Pharmacology Source Type: research

Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice
Abstract The aim of the current investigation was to assess the ability GFJ to modulate the pharmacokinetic profile of paracetamol following single or repeated administrations of GFJ in Sprague–Dawley rats. Diclofenac and carbamazepine were both used as positive controls. Rats received single GFJ or single distilled water doses or pretreated with three doses of GFJ prior to test drug administration. Blood samples were collected, processed and analyzed using validated HPLC methods, and pharmacokinetic data were constructed for each group. Increase in the bioavailability of both diclofenac and carbamazepine fo...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 30, 2014 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic and biodistribution study of eserine and pralidoxime chloride in rabbits following a single application of a transdermal patch
Abstract In the present study, a simple reverse-phase high-performance liquid chromatography method with diode array detection has been developed and validated for the simultaneous determination and quantification of eserine and pralidoxime chloride in rabbit plasma and its application to pharmacokinetic study. The pharmacokinetic study was performed after transdermal application of single patch in rabbits. The plasma levels of both drugs following transdermal application of single patch were maintained for 72 h after removal of the patch. The maximal concentrations (C max) of both drugs were signif...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 30, 2014 Category: Drugs & Pharmacology Source Type: research

A novel injection strategy of flurbiprofen axetil by inhibiting protein binding with 6-methoxy-2-naphthylacetic acid
This study focused on 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration–time curve (AUC) calculated from the free FP concentration, while there was ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 24, 2014 Category: Drugs & Pharmacology Source Type: research

Metabolism profiling of amino-noscapine
In conclusion, the metabolic pathway of amino-noscapine was elucidated in the present study using in vitro phase I incubation experiment, including the structural elucidation of metabolites and involved phase I drug-metabolizing enzymes. This information was helpful for the R&D of amino-noscapine. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 20, 2014 Category: Drugs & Pharmacology Source Type: research

Evaluation of clinical bradycardiac effect and respiratory adverse effect of β-blocking agents in coronary computed tomography angiography based on theoretical analysis
In this study, we analyzed the clinical bradycardiac effects and the adverse respiratory effects of five β-blocking agents (landiolol, esmolol, propranolol, metoprolol and atenolol) used for CCTA. The changes of the occupancy binding to β1 or β2 receptor of these drugs were calculated based on the receptor occupancy theory. Thereafter, we predicted both the rate of heart rate decline (▲HR) as a clinical effect and the rate of decrease in forced expiratory volume in 1 s (▲FEV1) as an adverse effect, by using the ternary complex model. The results showed that the drugs with ▲HR greater than 10 ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 16, 2014 Category: Drugs & Pharmacology Source Type: research

Initial dosing regimen of vancomycin to achieve early therapeutic plasma concentration in critically ill patients with MRSA infection based on APACHE II score
Abstract It is essential to assure the efficacy of antimicrobials at the initial phase of therapy. However, increasing the volume of distribution (Vd) of hydrophilic antimicrobials in critically ill patients leads to reduced antimicrobial concentration in plasma and tissue, which may adversely affect the efficacy of that therapy. The aim of the present study was to establish a theoretical methodology for setting an appropriate level for initial vancomycin therapy in individual patients based on Acute Physiology and Chronic Health Evaluation (APACHE) II score. We obtained data from patients who received intravenous...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 12, 2014 Category: Drugs & Pharmacology Source Type: research

Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine
Abstract The gene encoding uridine diphosphate glucuronosyltransferase (UGT) 1A4 shows considerable polymorphism. Several common drugs are metabolised by UGT1A4, among them lamotrigine (LTG). Experimental and clinical studies suggest that certain variants of UGT1A4 are associated with altered enzyme activity. However, results are conflicting. This clinical study aimed to investigate the frequencies of two common UGT1A4 variants, *2 (P24T) and *3 (L48V), and their potential effects on serum concentrations of LTG. The *2 variant was associated with a trend towards higher serum concentrations, while the *3 variant wa...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 10, 2014 Category: Drugs & Pharmacology Source Type: research

The role of CYP2C9 genetic polymorphism in carvedilol O-desmethylation in vitro
Abstract We aimed at investigating the role of CYP2C9 in carvedilol O-desmethylation and identifying the effect of 35 CYP2C9 allelic variants we found in Chinese Han population on the in vitro metabolism of carvedilol. Recombinant CYP2C9 and CYP2D6 microsomes of the wild type were used to test and verify the enzymes involved in carvedilol O-desmethylation. Recombinant CYP2C9 microsomes of distinguished genotypes were used to characterize the corresponding enzyme activity toward carvedilol. 2–100 μM carvedilol was incubated for 30 min at 37 °C. The products were detected using high-perfo...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 5, 2014 Category: Drugs & Pharmacology Source Type: research

The optimal oral dose selection of ibandronate in Japanese patients with osteoporosis based on pharmacokinetic and pharmacodynamic properties
Abstract Ibandronate is a drug widely used outside Japan for the treatment of osteoporosis. It is available in formulations for intermittent intravenous (i.v.) administration and for intermittent (once monthly) oral administration. Ibandronate was recently approved in Japan as an i.v. injection with a dosing regimen of 1.0 mg once a month. To establish the optimal dose for oral administration of ibandronate in Japanese osteoporotic patients, we investigated the pharmacokinetics of and pharmacodynamic response to ibandronate following oral and intravenous administrations to Japanese subjects. Ibandronate (20, ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 5, 2014 Category: Drugs & Pharmacology Source Type: research

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers
Abstract This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine–CYP1A2, repaglinide–CYP2C8, tolbutamide–CYP2C9, omeprazole–CYP2C19, dextromethorphan–CYP2D6, midazolam–CYP3A, acetaminophen–UGT1A1, 6&9 and 2B15, digoxin–P-gp, rosuvastatin–OATP1B1&3 and memantine–active renal transport). Blood was coll...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 3, 2014 Category: Drugs & Pharmacology Source Type: research

Placental profiling of UGT1A enzyme expression and activity and interactions with preeclampsia at term
Abstract Placental UDP-glucuronosyltransferase (UGT) enzymes have critical roles in hormone, nutrient, chemical balance and fetal exposure during pregnancy. Placental UGT1A isoforms were profiled and differences between preeclamptic (PE) and non-PE placental UGT expression determined. In third trimester villous placenta, UGT1A1, 1A4, 1A6 and 1A9 were expressed and active in all specimens (n = 10), but UGT1A3, 1A5, 1A7, 1A8 and 1A10 were absent. The UGT1A activities were comparable to human liver microsomes per milligram, but placental microsome yields were only 2 % of liver (1 mg/g of tissue vs...
Source: European Journal of Drug Metabolism and Pharmacokinetics - December 3, 2014 Category: Drugs & Pharmacology Source Type: research

CYP3A5*3 and MDR1 C3435T are influencing factors of inter-subject variability in rupatadine pharmacokinetics in healthy Chinese volunteers
Abstract Rupatadine (RUP) is an oral antihistamine and platelet-activating factor antagonist and is shown as the substrate of CYP3A5 and P-gp. The significant interindividual differences of CYP3A5 and P-gp often cause bioavailability differences of some clinical drugs. The present study is aimed to evaluate the effect of genetic polymorphisms of CYP3A5 and MDR1 on RUP pharmacokinetics in healthy male Chinese volunteer subjects. Blood samples were collected from 36 subjects before and after a single, oral RUP 10 mg dose. A PCR–RFLP assay was used to genotype CYP3A5*3 and assess MDR1 C3435T variation. A v...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 27, 2014 Category: Drugs & Pharmacology Source Type: research

In vitro metabolism of bencycloquidium bromide and its inhibitory effects on human P450 isoenzymes: implication of CYP2D6 , CYP2C19 and CYP3A4/5
Abstract Bencycloquidium bromide (BCQB) is a novel selective muscarinic M1/M3 receptor antagonist with potent therapeutic effects on rhinitis and chronic obstructive pulmonary disease. The metabolism of BCQB has been investigated in human liver microsomes and human recombinant P450 to elucidate the P450 isozymes responsible for its metabolism in human. Also, the metabolism pathway and the potency of BCQB in inhibiting CYP’s various isozymes in humans were investigated. The main biotransformation route of BCQB was NADPH-dependent oxidation. BCQB was metabolized oxidatively to four metabolites that were identi...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 26, 2014 Category: Drugs & Pharmacology Source Type: research

Inhibitory action of Epilobium hirsutum extract and its constituent ellagic acid on drug-metabolizing enzymes
In conclusion, inhibition of drug clearances leading to drug toxicity because of the lowered activity and expression of drug-metabolizing enzymes might be observed in the people who used EH as complementary herbal remedy that might be contributed by its EA content. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 26, 2014 Category: Drugs & Pharmacology Source Type: research

Effects of silymarin on the pharmacokinetics of atorvastatin in diabetic rats
Abstract The effect of silymarin (SMN) on the pharmacokinetics of atorvastatin in diabetic rats was evaluated. Male Wistar rats were assigned into two major groups and then sub-grouped according to the purposes of the study. The first major group was subdivided into three groups (n = 6) including control, non-treated diabetic and SMN-treated diabetic animals. In the first major group, metabolism of testosterone by the hepatic microsomes was studied. The second major group also was divided to three groups including atorvastatin-treated non-diabetic, atorvastatin-treated diabetic and diabetic animals whic...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

The influence of comedication on tacrolimus blood concentration in patients subjected to kidney transplantation: a retrospective study
Abstract Tacrolimus is an immunosuppressant used for the prevention of kidney allograft rejection. The effects of comedication on tacrolimus trough concentrations (TTC) in kidney transplant recipients, subjected to basic immunosuppressant regime consisting of tacrolimus, corticosteroids and mycophenolate mofetil were investigated. This retrospective case series study involved 208 of these patients, with the outpatient examination recorded in the database of patients, at the unit of monitoring, with a total of 5,011 such examinations. Binary logistic regression analysis has shown that calcium channel blockers,...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

Quantitative subcellular study of transferrin receptor-targeted doxorubicin and its metabolite in human breast cancer cells
This study provided the evidence that immunoisolation together with LC/MS/MS is an effective technique in subcellular investigations. (Source: European Journal of Drug Metabolism and Pharmacokinetics)
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents
Abstract The purpose of this study was to evaluate the impact of structural modifications on the 15-membered macrolactone ring and/or substituents on the in vitro ADME properties and in vivo pharmacokinetic (PK) profile for selected derivatives in rodents in comparison to azithromycin. Azithromycin and seven selected 15-membered macrolide derivatives, modified either by removal of the sugar moieties, replacement of the amine with a lactam, or addition of lipophilic substituents, were screened in several in vitro ADME assays and in vivo PK studies in rodents. In vitro ADME profiling included assessment of passive ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

The evaluation method for antiplatelet effect of acetylsalicylic acid
Abstract Reduced platelet aggregation by acetylsalicylic acid administration has been associated with adverse outcomes in patients with thrombotic diseases, thus it is important to determine aspirin resistance in those cases. The antiplatelet effect of acetylsalicylic acid is rarely measured, but it has many problems. The aim of this study was to find the evaluation method for antiplatelet effect after administration of acetylsalicylic acid. We developed a particle counting method based upon laser light scattering, and utilized the platelet aggregation agonists, collagen, at 0.25, 0.5 and 1.0 μg/mL, and a...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

Inhibition of murine cardiomyocyte respiration by amine local anesthetics
Abstract The hydrophobic amino acyl amide-linked local anesthetics (e.g., lidocaine and bupivacaine) impose potent cardiac toxicity and direct mitochondrial dysfunction. To investigate these adverse events, an in vitro system was employed to measure their effects on O2 consumption (cellular respiration) by murine myocardium. Specimens were collected from the ventricular myocardium and immediately immersed in ice-cold Krebs–Henseleit buffer saturated with 95 % O2:5 % CO2. O2 concentration was determined as a function of time from the phosphorescence decay rates of Pd(II)-meso-tetra-(4-sulfonatophen...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

The metabolism of trifluoperazine (TFP) exhibits atypical kinetic behavior in both human liver microsomes (HLMs) and monkey liver microsomes (MyLM)
Abstract Glucuronidation reaction of trifluoperazine (TFP) is a typical probe reaction to phenotype the activity of UDP-glucuronosyltransferase 1A4. The present study aims to compare the metabolic behavior of TFP in the liver microsomes from human and cynomolgus monkey, including the kinetic type and parameters. In vitro human liver microsome incubation system was used. The Eadie–Hofstee plot was used to determine the kinetic type. The results showed that the data for human liver microsomes (HLMs) and monkey liver microsomes (MyLMs)-catalyzed glucuronidation were best fit to the substrate inhibition model. ...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

Effect of silibinin on the pharmacokinetics of nitrendipine in rabbits
This study investigated the effect of silibinin on the pharmacokinetics of oral nitrendipine in rabbits. In first set of experiment, male New Zealand rabbits were pretreated with silibinin (50 mg/kg, PO) for 7 days and on last day nitrendipine (10 mg/kg, PO) was administered. In second set, both silibinin and nitrendipine were coadministered to examine acute effect of silibinin on nitrendipine pharmacokinetics. The plasma concentration of nitrendipine was estimated by high performance liquid chromatography and different pharmacokinetic parameters were calculated using WinNonlin® software. Coadministratio...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

The use of a prodrug approach to minimize potential CNS exposure of next generation quinoline methanols while maintaining efficacy in in vivo animal models
Abstract The use of mefloquine (MQ) for antimalarial treatment and prophylaxis has diminished largely in response to concerns about its neurologic side effects. An analog campaign designed to maintain the efficacy of MQ while minimizing blood–brain barrier (BBB) penetration has resulted in the synthesis of a prodrug with comparable-to-superior in vivo efficacy versus mefloquine in a P. berghei mouse model while exhibiting a sixfold reduction in CNS drug levels. The prodrug, WR319670, performed poorly compared to MQ in in vitro efficacy assays, but had promising in vitro permeability in an MDCK–MDR1 ce...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic evaluation of formulated levodopa methyl ester nasal delivery systems
The objective of this study was to investigate the pharmacokinetic characteristics of levodopa (l-dopa) from nasal powder formulations using highly water-soluble levodopa methyl ester hydrochloride (LDME). In vivo pharmacokinetic studies were carried out with formulated LDME nasal powders. After oral and intravenous administration of l-dopa and carbidopa and intranasal administration LDME to the rat, l-dopa concentrations were determined in plasma and the brain using high-performance liquid chromatography. The absolute bioavailabilities of nasal preparations with and without Carbopol were 82.4 and 66.7 %, respectively...
Source: European Journal of Drug Metabolism and Pharmacokinetics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research