Influence of gastrointestinal activity on the absorption of nilotinib.
Authors: Sasaki M, Aoyama T, Sugawara M, Takekuma Y Abstract Nilotinib has bioavailability (BA) of only about 25% or less. The purpose of this study was to evaluate the influence of gastrointestinal activity on the absorption of nilotinib. In order to change gastrointestinal activity, mosapride was used for enhancement and butylscopolamine was used for suppression. Experiments on oral administration of nilotinib using rats whose gastrointestinal activity was altered by mosapride or butylscopolamine were carried out. The results of oral administration of acetaminophen to rats with peristalsis movement changed showed...
Source: Drug Metabolism and Pharmacokinetics - November 19, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf ®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients.
The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients. Drug Metab Pharmacokinet. 2019 Oct 21;: Authors: Sukkha S, Chindavijak B, Nosoongnoen W, Phakdeekitchareon B, Kitiyakara C, Sumethkul V Abstract Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT reci...
Source: Drug Metabolism and Pharmacokinetics - November 16, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Relationships between plasma lactate, plasma alanine, genetic variations in lactate transporters and type 2 diabetes in the Japanese population.
Authors: Higuchi I, Kimura Y, Kobayashi M, Narumi K, Furugen A, Miyoshi H, Nakamura A, Yamada T, Atsumi T, Iseki K Abstract The present study aimed to characterize the relationships between plasma lactate, plasma alanine, monocarboxylate transporter (MCT) polymorphisms, and indices of diabetes in patients with type 2 diabetes (T2D) in Japan. Eighty-three patients with T2D were prospectively enrolled. The gluconeogenesis and glycogenolysis are enhanced and uptake of glucose is decreased in the T2D liver. Since the liver plays an important role in maintaining glucose metabolism, we examined the relationships between ...
Source: Drug Metabolism and Pharmacokinetics - November 16, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Short-lasting inhibition of hepatic uptake transporter OATP1B1 by tyrosine kinase inhibitor pazopanib.
Authors: Taguchi T, Masuo Y, Sakai Y, Kato Y Abstract Risk assessment of organic anion transporting polypeptide 1B1 (OATP1B1)-mediated drug-drug interactions (DDIs) is an integral part of drug development, but the difficult aspects in DDI prediction include complex mechanism of OATP1B1 inhibition. Pazopanib, an orally available tyrosine kinase inhibitor, exhibits OATP1B1 inhibition and clinically interacts with some OATP1B1 substrates, although quantitative analysis of DDI potential has not yet been performed. The purpose of the present study was to characterize the inhibitory effect of pazopanib on OATP1B1-mediate...
Source: Drug Metabolism and Pharmacokinetics - November 12, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Pharmacokinetic assessment of alprazolam-induced neonatal abstinence syndrome using physiologically based pharmacokinetic model.
In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data. PMID: 31699653 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - November 10, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Investigation on inhibitory effect of folic acid on methotrexate-induced epithelial-mesenchymal transition focusing  on dihydrofolate reductase.
In this study, the role of dihydrofolate reductase (DHFR), a target of MTX, in FA-mediated inhibition of MTX-induced EMT was evaluated. The inhibitory effects of FA and tetrahydrofolate (THF), a metabolite of FA produced by DHFR, on MTX-induced increases in mRNA expression of α-SMA, an EMT marker, were compared. The IC50 values of FA and THF for DHFR were 103.3 and 19.4 μM, respectively. In contrast, DHFR knockdown did not alter the mRNA expression of α-SMA. Notably, the inhibitory effect of FA, but not THF, on MTX-induced EMT was blunted in DHFR knockdown cells. These results suggested that DHFR may no...
Source: Drug Metabolism and Pharmacokinetics - October 13, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Riboflavin transport mediated by riboflavin transporters (RFVTs/SLC52A) at the rat outer blood-retinal barrier.
Authors: Kubo Y, Miki S, Akanuma SI, Hosoya KI Abstract The previous in vivo study revealed the carrier-mediated transport of riboflavin (vitamin B2) across the blood-retinal barrier (BRB). In the present study, the blood-to-retina supply of riboflavin across the outer BRB was assessed in RPE-J cells, a rat-derived in vitro cell model of the outer BRB that is formed by the retinal pigment epithelial cells. In the directional uptake analysis on collagen-coated Transwell® inserts, RPE-J cells showed higher basal-to-cell (B-to-C) uptake (22.8 μL/mg protein) of [3H]riboflavin than apical-to-cell (...
Source: Drug Metabolism and Pharmacokinetics - October 13, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Microdosing clinical study to clarify pharmacokinetic and pharmacogenetic characteristics of atorvastatin in Japanese hypercholesterolemic patients.
Authors: Lee N, Maeda K, Fukizawa S, Ieiri I, Tomaru A, Akao H, Takeda K, Iwadare M, Niwa O, Masauji T, Yamane N, Kajinami K, Kusuhara H, Sugiyama Y Abstract The present study investigated whether the clinical pharmacokinetics of atorvastatin can be predicted from the results of microdosing study in Japanese patients with hypercholesterolemia whose SLCO1B1 and ABCG2 polymorphisms were analyzed. Forty seven statin-naive patients clinically indicated to LDL cholesterol-lowering therapy with atorvastatin were enrolled in a two-period crossover study. Microdose (100 μg) of atorvastatin was orally administered f...
Source: Drug Metabolism and Pharmacokinetics - October 10, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Risk of CYP2C9 induction analyzed by a relative factor approach with human hepatocytes.
Authors: Endo-Tsukude C, Kato M, Kaneko A, Iida S, Kuramoto S, Ishigai M, Hamada A Abstract By using the Relative Factor (RF) method-a method that can simply assess cytochrome P450 (CYP) induction risk based on a maximum induction effect model-we evaluated the risk of CYP2C9 induction and examined its relationship with risk of CYP3A4 induction. In cryopreserved human hepatocytes, the magnitude of CYP2C9 induction by eight drugs known to induce CYP3A4 was lower than the magnitude of CYP3A4 induction, but the magnitudes of induction of both were correlated. The RF values determined for CYP2C9 had a one-to-one linear ...
Source: Drug Metabolism and Pharmacokinetics - October 2, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Quantitative investigation of hepatobiliary transport of [11C]telmisartan in humans by PET imaging.
Authors: Maeda K, Ohnishi A, Sasaki M, Ikari Y, Aita K, Watanabe Y, Kusuhara H, Sugiyama Y, Senda M Abstract The pharmacokinetics of telmisartan are nonlinear within the clinical dose range. To identify the underlying mechanism of this nonlinearity, we conducted a PET study in healthy subjects using [11C]telmisartan. Eight healthy male subjects were enrolled in a 2-way crossover study. PET imaging was performed after intravenous administration of [11C]telmisartan with or without a 1-h oral predose of two 40 mg Micardis® tablets. About 60% of the injected [11C]telmisartan accumulated in the liver within 10&...
Source: Drug Metabolism and Pharmacokinetics - October 2, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Solving the interactions of steroidal ligands with CYP3A4 using a grid-base template system.
Authors: Goto T, Tohkin M, Yamazoe Y Abstract Using over fifty steroidal ligands, CYP3A4 Template system established in our previous study (DMPK 34: 113-125, 2019) has been evaluated for the applicability for prediction of regioselective metabolisms of steroids in the present study. Plural regional interactions near Site of Oxidation of CYP3A4 (Slide-down and Adaptation) are newly defined for steroid ligands in addition to previously characterized Trigger- and IJL-interactions on Template. Interaction of steroids at ring-A with CYP3A4 residue (Front-residue), at the facial side of Ring B of Template, determined the...
Source: Drug Metabolism and Pharmacokinetics - September 30, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Population pharmacokinetic and exposure-response analyses of guanfacine in Japanese pediatric ADHD patients.
Authors: Tsuda Y, Matsuo Y, Matsumoto S, Wajima T Abstract Guanfacine hydrochloride extended-release tablet (GXR) is approved for child and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). The aims of this study were to develop a population pharmacokinetic model of guanfacine after administration of GXR and to evaluate factors influencing the pharmacokinetics of guanfacine in pediatric ADHD patients. A population pharmacokinetic analysis was performed using 3231 plasma concentration data items of guanfacine for pediatric ADHD patients aged 6-17 years obtained from clinical studies in Japan ...
Source: Drug Metabolism and Pharmacokinetics - September 30, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Metabolomics study on the therapeutic effect of traditional Chinese medicine Xue-Fu-Zhu-Yu decoction in coronary heart disease based on LC-Q-TOF/MS and GC-MS analysis.
Authors: Yi M, Li Q, Zhao Y, Nie S, Wu N, Wang D Abstract The present study aims is to investigate the metabolic mechanism of Xue-Fu-Zhu-Yu decoction (XFZYD) in the treatment of blood-stasis syndrome in Coronary Heart Disease (CHD). To that end, 30 CHD patients with Blood-Stasis Syndrome (BSS) and 20 healthy subjects were enrolled. LC-Q-TOF/MS analysis determined that in comparison between CHD with BSS patients (Group A) and healthy subjects (Group C), 59 significantly differential metabolites in the positive mode and 18 significantly differential metabolites in the negative mode. The metabolite constituents in the...
Source: Drug Metabolism and Pharmacokinetics - September 3, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Genetic variants of flavin-containing monooxygenase 3 (FMO3) derived from Japanese subjects with the trimethylaminuria phenotype and whole-genome sequence data from a large Japanese database.
Authors: Shimizu M, Yoda H, Nakakuki K, Saso A, Saito I, Hishinuma E, Saito S, Hiratsuka M, Yamazaki H Abstract Flavin-containing monooxygenase 3 (FMO3) is a polymorphic xenobiotic- and dietary compound-metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped 428 Japanese subjects using traditional urinary phenotyping assays and identified two subjects with
Source: Drug Metabolism and Pharmacokinetics - August 13, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Evaluation of transporter-mediated hepatobiliary transport of newly developed 18F-labeled pitavastatin derivative, PTV-F1, in rats by PET imaging.
Authors: Kimura H, Yagi Y, Mikamo M, Kazuya M, Kagawa S, Arimitsu K, Higashi T, Nishii R, Ono M, Nakamoto Y, Togashi K, Kusuhara H, Saji H Abstract Quantitative evaluations of the functions of uptake and efflux transporters directly in vivo is desired to understand an efficient hepatobiliary transport of substrate drugs. Pitavastatin is a substrate of organic anion transporting polypeptides (OATPs) and canalicular efflux transporters; thus, it can be a suitable probe for positron-emission tomography (PET) imaging of hepatic transporter functions. To characterize the performance of [18F]PTV-F1, an analogue of p...
Source: Drug Metabolism and Pharmacokinetics - July 25, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Possible involvement of the competition for the transcriptional coactivator glucocorticoid receptor-interacting protein 1 in the inflammatory signal-dependent suppression of PXR-mediated CYP3A induction in  vitro.
Possible involvement of the competition for the transcriptional coactivator glucocorticoid receptor-interacting protein 1 in the inflammatory signal-dependent suppression of PXR-mediated CYP3A induction in vitro. Drug Metab Pharmacokinet. 2019 Apr 19;: Authors: Okamura M, Shizu R, Hosaka T, Sasaki T, Yoshinari K Abstract Pregnane X receptor (PXR) is a xenobiotic-responsive transcription factor that plays a pivotal role in drug metabolism and disposition in livers and intestines through regulating the expression of drug metabolizing enzymes and transporters. It is well known that PXR-mediated induc...
Source: Drug Metabolism and Pharmacokinetics - July 11, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

In  vitro bile acid-dependent hepatocyte toxicity assay system using human induced pluripotent stem cell-derived hepatocytes: Current status and disadvantages to overcome.
In vitro bile acid-dependent hepatocyte toxicity assay system using human induced pluripotent stem cell-derived hepatocytes: Current status and disadvantages to overcome. Drug Metab Pharmacokinet. 2019 May 10;: Authors: Sakai Y, Iwao T, Susukida T, Nukaga T, Takemura A, Sekine S, Ito K, Matsunaga T Abstract Cholestatic drug-induced liver injury (DILI) is a type of hepatotoxicity. Its underlying mechanisms are dysfunction of bile salt export pump (BSEP) and multidrug resistance-associated protein 2/3/4 (MRP2/3/4), which play major roles in bile acid (BA) excretion into the bile canaliculi and blood...
Source: Drug Metabolism and Pharmacokinetics - July 11, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Characterization of human UGT2A3 expression using a prepared specific antibody against UGT2A3.
In this study, we prepared a specific antibody against human UGT2A3 and evaluated the relative expression of UGT2A3 in the human liver, small intestine, and kidney. Western blot analysis indicated that this antibody is specific to UGT2A3 because it did not cross-react with other human UGT isoforms or rodent UGTs. UGT2A3 expression in the human small intestine was higher than that in the liver and kidney. Via treatment with endoglycosidase, it was clearly demonstrated that UGT2A3 was N-glycosylated. UGT2A3 protein levels were significantly correlated with UGT2A3 mRNA levels in a panel of 28 human liver samples (r = 0.64, p 
Source: Drug Metabolism and Pharmacokinetics - July 4, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Effects of food type on the extent of drug-drug interactions between activated charcoal and phenobarbital in rats.
In conclusion, the influence of food intake on the extent of DDI between phenobarbital and activated charcoal was found to differ among the types of food concomitantly ingested. PMID: 31255507 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - July 2, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Carboxylesterase catalyzed 18O-labeling of carboxylic acid and its potential application in LC-MS/MS based quantification of drug metabolites.
Authors: Yu ZJ, Roesner JM, Lutz R, Liang Y, Baker J, Smith DM, Fan PW Abstract LC-MS quantification of drug metabolites is sometimes impeded by the availability of internal standards that often requires customized synthesis and/or extensive purification. Although isotopically labeled internal standards are considered ideal for LC-MS/MS based quantification, de novo synthesis using costly isotope-enriched starting materials makes it impractical for early stage of drug discovery. Therefore, quick access to these isotope-enriched compounds without chemical derivatization and purification will greatly facilitate LC-MS...
Source: Drug Metabolism and Pharmacokinetics - June 28, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Pharmacokinetics and bioequivalence of low-dose clopidogrel in healthy Chinese volunteers under fasted and fed conditions.
Authors: Gong L, Fu C, Bi L, Kuang Y, Guo C, Wei G, Yan Z, Huang J, Yang G Abstract Clopidogrel is an antiplatelet drug whose performance at a low dose (25 mg) have not been evaluated in Chinese patients, who may be subject to different effects from Caucasians. We carried out this evaluation and compared a generic (Taijia) and a reference drug (Plavix®). We evaluated Taijia and Plavix® in 128 subjects, with 64 in a fasted state and 64 receiving a high-fat diet, and computed Cmax, AUC0-∞, and AUC0-t. Reference-scaled average bioequivalence (RSABE) methods and average bioequivalence (ABE) methods w...
Source: Drug Metabolism and Pharmacokinetics - June 28, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Estimation of changes in serum creatinine and creatinine clearance caused by renal transporter inhibition in healthy subjects.
Authors: Nakada T, Kudo T, Kume T, Kusuhara H, Ito K Abstract Creatinine is excreted into urine by glomerular filtration and renal tubular secretion through drug transporters such as organic anion transporter 2 (OAT2), organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. We aimed to investigate whether our method for estimating percentage changes in serum creatinine concentration (SCr) and creatinine clearance (CLcre) from the baseline is applicable for studying renal transporter inhibitors. We tested 14 compounds (cimetidine, cobicistat, dolutegravir, dronedarone...
Source: Drug Metabolism and Pharmacokinetics - June 11, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Organic anion-transporting polypeptide 1a4-mediated heterogeneous distribution of sulforhodamine-101 in rat hepatic lobules.
This study aimed to investigate sulforhodamine-101 (SR-101) distribution in the rat liver, determine the molecules responsible for the distribution, and delineate the manner of distribution. After intravenous SR-101 administration, its distribution in frozen rat hepatic sections was examined. SR-101-derived signals were detected in regions around the hepatic central vein (CV), where immunohistochemistry (IHC) indicated high Oatp1a4 expression. The signals decreased with treatment by digoxin, a specific substrate for Oatp1a4. In vitro studies using isolated rat hepatocytes and rat Oatp1a4-expressing Xenopus laevis oocy...
Source: Drug Metabolism and Pharmacokinetics - June 10, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Comparison of mRNA expression profiles of drug-metabolizing enzymes and transporters in fresh and cryopreserved cynomolgus monkey hepatocytes.
In this study, freshly isolated and cryopreserved cynomolgus monkey hepatocytes were seeded on Cell-able® plates with feeder cells to form spheroids and were cultured for 28 days. As a control, hepatocytes were also cultured with or without feeder cells on collagen-coated plates. We verified the mRNA expression levels of drug-metabolizing enzyme-related genes and the leakage of enzymes (AST, ALT, LDH, and γ-GTP) as indicators of cell survival. As a result, the patterns of target mRNA expression in fresh and cryopreserved hepatocytes were very similar during the culture period between culture methods. mRNA express...
Source: Drug Metabolism and Pharmacokinetics - June 10, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Prediction of regioselectivity and preferred order of metabolisms on CYP1A2-mediated reactions part 3: Difference in substrate specificity of human and rodent CYP1A2 and the refinement of predicting system.
Authors: Yamazoe Y, Yoshinari K Abstract Differences in CYP1A2-mediated metabolisms in human, rat and mouse have been analyzed with Template of human CYP1A2 established in our previous studies (Drug Metab Pharmacokinet 31:363, 2016 and 32:229, 2017). Using more than 25 chemicals including phenanthrene, MeIQx, PhIP, caffeine and furafylline, Template for human CYP1A2 was found to be applicable for rat and mouse CYP1A2 reactions with the consideration of five distinct regional interactions: 1) Expanded use of Ring D region of pro-metabolized molecules and also of trigger molecules, 2) acceptance of secondary amino gr...
Source: Drug Metabolism and Pharmacokinetics - May 29, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Rifamycin SV exhibits strong anti-inflammatory in  vitro activity through pregnane X receptor stimulation and NFκB inhibition.
This study aimed to further evaluate the anti-inflammatory activities of rifamycin by analyzing its effect on two key regulators of inflammation: PXR and NFκB. Rifamycin stimulated PXR transcriptional activity in two PXR reporter cell lines and induced expression of two genes known to be regulated by PXR and are directly involved in cellular detoxification: CYP3A4 and PgP. Moreover, CYP3A4 metabolic activity was induced by rifamycin in HepG2 cells. Rifamycin also antagonized TNFα and LPS-induced NFκB activities and inhibited IL1β-induced synthesis of inflammatory chemokine, IL8. Although reciprocal r...
Source: Drug Metabolism and Pharmacokinetics - May 19, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Applications of MALDI mass spectrometry imaging for pharmacokinetic studies during drug development.
Authors: Nishidate M, Hayashi M, Aikawa H, Tanaka K, Nakada N, Miura SI, Ryu S, Higashi T, Ikarashi Y, Fujiwara Y, Hamada A Abstract The concentration and distribution of a drug or its metabolites in tissues are key factors for understanding drug efficacy or toxicity. Conventional pharmacokinetic studies show that the plasma concentration of a drug is often unrelated to the intra-tissue concentration. Moreover, it is difficult to predict the distribution of a drug in tissues, particularly those with complex structures, even though the overall tissue concentration is measured by using homogenizing procedures. Mass s...
Source: Drug Metabolism and Pharmacokinetics - May 19, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Quantitative prediction of hepatic CYP3A activity using endogenous markers in healthy subjects after administration of CYP3A inhibitors or inducers.
This study aimed to evaluate the previously constructed CYP3A activity prediction model after administration of CYP3A inhibitors and inducers and to modify the model for better prediction of CYP3A activity. Healthy male subjects received the following study drugs during three study periods: midazolam alone (control phase); midazolam with 200 mg of itraconazole (CYP3A inhibition phase); and midazolam with 150 mg of rifampicin (CYP3A induction phase). We quantified the concentrations of several endogenous CYP3A markers in both urine and plasma using gas chromatography-mass spectrometry. The urinary markers, includi...
Source: Drug Metabolism and Pharmacokinetics - May 16, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Influences of cytochrome b5 expression and its genetic variant on the activity of CYP2C9, CYP2C19 and CYP3A4.
The objective of the present study was to investigate the effects of cytochrome b5 (cytb5) on the drug metabolism catalyzed by CYP2C9, CYP2C19 and CYP3A4. Activities of CYP2C9, CYP2C19, and CYP3A4 were determined by using the prototypical substrates tolbutamide, omeprazole and midazolam, respectively. Cytb5 protein and mRNA contents showed large inter-individual variations with 11- and 6-fold range, respectively. All of three P450s showed an increased activity in proportion to the amount of cytb5 expression. Particularly, CYP3A4 showed the strongest correlation between cytb5 protein amount and the activity, followed by CYP...
Source: Drug Metabolism and Pharmacokinetics - April 19, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Inhibitory kinetics of fruit components on CYP2C19 activity.
In conclusion, these findings suggest that food containing these components has the potential to evoke drug-food interactions caused by the MBI of intestinal CYP2C19 activity in the clinical setting. PMID: 30979536 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - April 15, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Correlation of MCT1 and ABCC2 gene polymorphisms with valproic acid resistance in patients with epilepsy on valproic acid monotherapy.
This study is to investigate the influence of single nucleotide polymorphisms (SNPs) in multidrug transporters on VPA responses in Han Chinese epilepsy patients on VPA monotherapy. Twelve SNPs involved in VPA transport pathways, including ABCC2, ABCC4, ABCG2, MCT1, MCT2 and OATP2B1 were genotyped in 153 Han Chinese epilepsy patients. We found that among all the patients, MCT1 rs60844753 CC carriers have higher incidence of VPA-resistance than CG carriers (P = 0.05), and in subgroup of generalized seizure, ABCC2 rs3740066 CC carriers had higher frequency of VPA resistance than TC + TT carriers (P =&...
Source: Drug Metabolism and Pharmacokinetics - April 8, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Retraction notice to "Population pharmacokinetic and pharmacodynamic analysis of bosutinib" [Drug Metab Pharmacokinet 29 (2014) 441-448].
This article [1] has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors. According to the authors, their recent analyses have revealed that the model presented may lead to inaccurate conclusions, particularly regarding the peripheral volume of distribution and beta half-life of the compound. Since the model is critical to the article and its conclusion, the editor has approved to retract the article. PMID: 30922682 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - March 30, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

In  vitro metabolic stability and biotransformation of isosteviol in human and rat liver fractions.
This study determined the metabolic stability of isosteviol in human liver microsomes and H9c2 cell line, and the identity of its metabolites in human and rat liver fractions. Isosteviol was largely unmetabolized in H9c2 cells and in NADPH-only supplemented human liver fractions, suggesting a very limited contribution of phase I biotransformation to its hepatic clearance. The in vitro half-life of isosteviol in UDPGA-only supplemented medium was observed to be 24.9 min with an estimated intrinsic clearance of 0.349 mL/min/kg in man. Analysis by LC-MS/MS and Q-tof showed that isosteviol is mainly metabolised ...
Source: Drug Metabolism and Pharmacokinetics - March 20, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Studies on the L-2-hydroxy-acid oxidase 2 catalyzed metabolism of S-mandelic acid and its analogues.
Authors: Zhang Y, Su C, Lei J, Chen L, Hu H, Zeng S, Yu L Abstract Mandelic acid (MA) is generally used as a biomarker of the exposure of styrene, which is classified as a class of hazardous environmental pollutants, and also used as an important chiral intermediate in pharmaceutical industry. The previous studies have found the excretion of phenylglyoxylic acid (PGA) in human and rat, a metabolite of MA, was mainly from S-MA rather than R-MA. The metabolic mechanism, however, is not clear. In order to explore the possible metabolic mechanism, the enzyme types involved in the stereoselectivity metabolism of MA were...
Source: Drug Metabolism and Pharmacokinetics - March 17, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Current status and future perspective on preclinical pharmacokinetic and pharmacodynamic (PK/PD) analysis: Survey in Japan pharmaceutical manufacturers association (JPMA).
Authors: Goto A, Abe S, Koshiba S, Yamaguchi K, Sato N, Kurahashi Y Abstract Preclinical pharmacokinetic/pharmacodynamic (PK/PD) analysis is an efficient tool for the translational research and proof of mechanism/concept in animals. The questionnaire survey on the practice of preclinical PK/PD analysis was conducted in the member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). According to the survey, 60% of companies conducted preclinical PK/PD analysis and its impact for drug development was different between each of the companies. The frequently analyzed therapeutic areas of preclinical P...
Source: Drug Metabolism and Pharmacokinetics - March 6, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Uric acid analogue as a possible xenobiotic marker of uric acid transporter Urat1 in rats.
Authors: Arakawa H, Amezawa N, Katsuyama T, Nakanishi T, Tamai I Abstract The inhibitor of uric acid reabsorptive transporter URAT1 in kidney is drawing attention as a drug target for hyperuricemia. However, it is difficult to evaluate efficacy of URAT1 inhibitors in vivo using laboratory animals due to species difference in uric acid metabolism. In the present study, the usefulness of exogenously administering uric acid analogues resistant to uricase was investigated for in vivo evaluation of transport activity of rUrat1 in rats. Uptake of examined four uric acid analogues by rUrat1-expressing Xenopus oo...
Source: Drug Metabolism and Pharmacokinetics - March 5, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Proteomic analysis of small intestinal epithelial cells in antibiotic-treated mice: Changes in drug transporters and metabolizing enzymes.
This study investigated changes in the protein levels of drug transporters and metabolizing enzymes in the small intestines of antibiotic-treated mice by proteomic analysis. After the oral administration of non-absorbable antibiotics (vancomycin and polymyxin B) for 5 days, 15 drug transporter or metabolizing enzyme proteins had significantly changed levels among 1780 proteins identified in small intestinal epithelial cells. Of these, the levels of peptide transporter 1 (Pept1), multidrug resistance protein 1a (Mdr1a), and multidrug resistance-associated protein 2 (Mrp2) were increased approximately 2-fold. In addition, th...
Source: Drug Metabolism and Pharmacokinetics - March 5, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Antibody-based therapeutics.
Authors: Tachibana T, Kuwabara T PMID: 30771882 [PubMed - in process] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - February 19, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Appreciation to Reviewers 2018.
Authors: PMID: 30771883 [PubMed - in process] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - February 19, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Minimal contribution of P-gp on the low brain distribution of naldemedine, a peripherally acting μ-opioid receptor antagonist.
In this study, we investigated the contribution of P-glycoprotein (P-gp) on the brain distribution of naldemedine. Naldemedine tosylate showed acceptable oral absorption in rats. Following a single oral administration of [14C]-naldemedine tosylate to rats and ferrets, little radioactivity was detected in the region protected by the blood-brain barrier (BBB). In the assessment using Caco-2 cells, it was determined that naldemedine is a substrate for P-gp. The contribution of P-gp to the brain distribution of naldemedine was assessed using multidrug resistance 1a/b (mdr1a/b) knockout mice. While the brain-to-plasma conc...
Source: Drug Metabolism and Pharmacokinetics - February 17, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Sulfate conjugates are the major metabolites in rats administrated with sesamin.
In this study, the metabolites of sesamin in rats administrated with sesamin (100 mg/kg b.w.) were analyzed without sulfatase/β-glucuronidase treatment. Two sulfate conjugates of sesamin monocatechol (SC-1) were detected in the liver and plasma. Their Cmax values were 5- and 10-times higher than that of sesamin itself. The Vmax/Km values for sulfate conjugation in the cytosol fraction of human liver were 1.7-times larger than that in the cytosol fraction of rat liver, suggesting that sulfate conjugation also occurs in human liver. The recombinant human proteins SULT1A1, 1A3, 1B1, and 1E1 expressed in Saccharomyce...
Source: Drug Metabolism and Pharmacokinetics - February 17, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Establishment of rat liver microsome-hydrogel system for in  vitro phase II metabolism and its application to study pharmacological effects of UGT substrates.
Establishment of rat liver microsome-hydrogel system for in vitro phase II metabolism and its application to study pharmacological effects of UGT substrates. Drug Metab Pharmacokinet. 2019 Jan 30;: Authors: Zhang Z, Ma G, Xue C, Sun H, Wang Z, Xiang X, Cai W Abstract Studies on the efficacy evaluation of UDP-glucuronosyltransferases (UGTs) substrates often ignore the existence of active metabolites. However, the present study aims to establish an in-vitro Phase II metabolism system to predict their pharmacological effects after metabolism. Rat liver microsomes (RLMs) encapsulated in a F127'-Acr-Bi...
Source: Drug Metabolism and Pharmacokinetics - February 14, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

A letter of reply to the commentary by Dr. Stamp et  al.
A letter of reply to the commentary by Dr. Stamp et al. Drug Metab Pharmacokinet. 2018 Dec 15;: Authors: Ichidaa K PMID: 30709683 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - February 4, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Reconstitution of CYP3A4 active site through assembly of ligand interactions as a grid-template: Solving the modes of the metabolism and inhibition.
Authors: Yamazoe Y, Goto T, Tohkin M Abstract A hexagonal-grid based template system has been developed to a predicting tool of CYP3A4-mediated reactions through the reconstitution of the active site with the assembly of the ligands. Simultaneous interactions of flattened-shape ligands at two sites of CYP3A4, oxidizing- and triggering-sites, are essential ideas, which were supported in the simulation results of various ligands on the template. The interactions were accomplished with either uni-molecule bindings or bi-molecule bindings with ligands termed pro-metabolized and trigger molecules. The template shape was...
Source: Drug Metabolism and Pharmacokinetics - January 15, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties.
Authors: Imamura CK Abstract Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation which is protected by neonatal Fc-receptor or mediated by antigenic target. There is a wide-interindividual variability in mAbs exposure due to target burden and other factors affecting unique their pharmacokinetics. It has been reported that higher exposures are correlated with better clinical outcomes of various therapeutic mAbs....
Source: Drug Metabolism and Pharmacokinetics - January 5, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies.
Authors: Ishii-Watabe A, Kuwabara T Abstract The concept of biosimilar was established in the early 2000s in EU. Currently, the regulatory framework for biosimilar has also been established in the US, Japan, and other countries. As of 2018, biosimilars for infliximab, adalimumab, rituximab, trastuzumab, and bevacizumab have been approved. During the development of a biosimilar, product quality should be evaluated and compared with those of the reference product extensively. Among the quality attributes of therapeutic antibodies, FcRn binding and related structures are well known to affect the pharmacokinetic profil...
Source: Drug Metabolism and Pharmacokinetics - January 4, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Transport of 2,4-dichloro phenoxyacetic acid by human Na+-coupled monocarboxylate transporter 1 (hSMCT1, SLC5A8).
Authors: Sugio K, Inoda D, Masuda M, Azumaya I, Sasaki S, Shimono K, Ganapathy V, Miyauchi S Abstract Using X. laevis oocyte expression system, we investigated whether human Na+-coupled monocarboxylate transporter 1 (SLC5A8, hSMCT1) is involved in 2,4-dichlorophenoxyacetate (2,4-D) uptake by the renal tubular epithelial cells. 2,4-D is a herbicide that causes nephrotoxicity. Heterologous expression of hSMCT1 in X. laevis oocytes conferred the ability to take up 2,4-D; the induced uptake process was Na+-dependent and electrogenic. The Na+-dependent uptake of 2,4-D was inhibited not only by known hSMCT1 sub...
Source: Drug Metabolism and Pharmacokinetics - December 26, 2018 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Pharmacokinetics of protein and peptide conjugates.
Authors: Bumbaca B, Li Z, Shah DK Abstract Protein and peptide conjugates have become an important component of therapeutic and diagnostic medicine. These conjugates are primarily designed to improve pharmacokinetics (PK) of those therapeutic or imaging agents, which do not possess optimal disposition characteristics. In this review we have summarized preclinical and clinical PK of diverse protein and peptide conjugates, and have showcased how different conjugation approaches are used to obtain the desired PK. We have classified the conjugates into peptide conjugates, non-targeted protein conjugates, and targeted p...
Source: Drug Metabolism and Pharmacokinetics - December 24, 2018 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development.
Authors: Glassman PM, Balthasar JP Abstract Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolism, and elimination) is crucial in developing safe and efficacious therapeutics. In the present review, we discuss the use of physiologically-based pharmacokinetic (PBPK) models as an approach to characterize the in vivo behavior of mAbs, in the context o...
Source: Drug Metabolism and Pharmacokinetics - December 15, 2018 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers.
This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2.2, 1.7 and 1.58-times greater than the corresponding values in OATP1B1 *1b/*1b, respectively, whereas that of fluvastatin was identi...
Source: Drug Metabolism and Pharmacokinetics - December 14, 2018 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research