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Jincheng Yang, Maulik Patel, Mina Nikanjam, Edmund V Capparelli, Shirley M Tsunoda, Howard E Greenberg, Scott R Penzak, S Aubrey Stoch, Joseph S Bertino, Anne N Nafziger, Joseph D Ma
Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated...
April 17, 2018: Journal of Clinical Pharmacology
Unji Lee, Mi Hye Kwon, Hee Eun Kang
1. Plasma lipid profile abnormalities in hyperlipidemia can potentially alter the pharmacokinetics of a drug in a complex manner. To evaluate these pharmacokinetic alterations in hyperlipidemia and to determine the underlying mechanism(s), poloxamer 407-induced hyperlipidemic rats (HL rats), a well-established animal model of hyperlipidemia have been used. 2. In this review, we summarize findings on the pathophysiological and gene expression changes in drug-metabolizing enzymes and transporters in HL rats. We discuss pharmacokinetic changes in drugs metabolized primarily via hepatic cytochrome P450 (CYPs) in terms of alterations in hepatic intrinsic clearance (CL'int ), free fraction in plasma (fu ), and hepatic blood flow rate (QH ), depending on the hepatic excretion ratio, as well as drugs eliminated primarily by mechanisms other than hepatic CYPs...
April 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Gabriela Dovrtelova, Ondrej Zendulka, Kristyna Noskova, Jan Jurica, Ondrej Pes, Jan Dusek, Alejandro Carazo, Iveta Zapletalova, Natasa Hlavacova, Petr Pavek
The endocannabinoid system is important for many physiological and pathological processes, but its role in the regulation of liver cytochromes P450 (CYPs) is still unknown. We studied the influence of the endocannabinoid oleamide on rat and human liver CYPs. Oleamide was administered i.p. to rats at doses of 0.1, 1 and 10 mg/kg/day for 7 days. The content and activity of key CYPs was evaluated in rat liver microsomes. Moreover, its interactions with nuclear receptors regulating CYP genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in vitro CYP inhibition assays...
April 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Diana Busch, Anja Fritz, Lars Ivo Partecke, Claus-Dieter Heidecke, Stefan Oswald
Many orally administered drugs are subject to first-pass metabolism by cytochrome P450 (CYP) enzymes and uridine 5'-diphospho-glucuronosyltransferases (UGT). While their hepatic activity is well characterized, respective information about the intestine are very scare due to limited availability of tissue, very low microsomal protein content and the heterogeneity of the individual segments. As a consequence, determination of enzyme kinetic parameters is challenging. It was therefore the aim of this study to develop a sensitive liquid chromatography tandem mass spectrometry method for the simultaneous quantification of CYP and UGT metabolites formed by clinically relevant intestinal biotransformation enzymes: 4-hydroxydiclofenac (CYP2C9), 5-hydroxyomeprazole (CYP2C19), dextrorphan (CYP2D6), 1-hydroxymidazolam (CYP3A), ezetimibe glucuronide (UGT1A) and naloxone glucuronide (UGT2B7)...
April 5, 2018: Journal of Pharmaceutical and Biomedical Analysis
Amy L Pasternak, Lu Zhang, Daniel L Hertz
Tacrolimus is prescribed to the majority of transplant recipients to prevent graft rejection, and although patients are maintained on oral administration, nonoral routes of administration are frequently used in the initial post-transplant period. CYP3A5 genotype is an established predictor of oral tacrolimus dose requirements, and clinical guideline recommendations exist for CYP3A5-guided dose selection. However, the association between CYP3A5 and nonoral tacrolimus administration is currently poorly understood, and differs from the oral tacrolimus relationship...
April 9, 2018: Pharmacogenomics
Chen-Chun Zhong, Feng Chen, Jun-Ling Yang, Wei-Wei Jia, Li Li, Chen Cheng, Fei-Fei Du, Su-Ping Zhang, Cheng-Ying Xie, Na-Ting Zhang, Olajide E Olaleye, Feng-Qing Wang, Fang Xu, Li-Guang Lou, Dong-Ying Chen, Wei Niu, Chuan Li
Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22...
April 5, 2018: Acta Pharmacologica Sinica
Jaydeep Yadav, Ken Korzekwa, Swati Nagar
Time-dependent inactivation (TDI) of CYPs is a leading cause of clinical drug-drug interactions (DDIs). Current methods tend to over-predict DDIs. In this study, a numerical approach was used to model complex CYP3A TDI in human liver microsomes. Inhibitors evaluated include troleandomycin (TAO), erythromycin (ERY), verapamil (VER) and diltiazem (DTZ) along with primary metabolites N-demethyl erythromycin (NDE), norverapamil (NV), and N-desmethyl diltiazem (NDD). Complexities incorporated in the models included multiple binding kinetics, quasi-irreversible inactivation, sequential metabolism, inhibitor depletion, and membrane partitioning...
April 2, 2018: Molecular Pharmaceutics
Yukihiro Nomura, Hiroyuki Murata, Hiroaki Sasai, Akihiko Kimura, Takao Kurosawa, Takahiro Sasaki, Tsuyoshi Murai
Unusual bile acids (1β-hydroxylated bile acids), particularly 1β-hydroxyl-cholic acid (CA-1β-ol) and 1β-hydroxyl-chenodeoxycholic acid (CDCA-1β-ol), have been detected in the urine of infants. These acids are conjugated with amino acids, such as taurine, and are then excreted mainly via the urine. CA-1β-ol and CDCA-1β-ol are the predominant bile acids during infancy and are present in relatively large amounts in the urine. However, the biosynthetic pathway of 1β-hydroxylated bile acids in infants remains unclear...
2018: Biological & Pharmaceutical Bulletin
Alexander Valerevich Kryukov, Dmitry Alekseevich Sychev, Denis Anatolevich Andreev, Kristina Anatolievna Ryzhikova, Elena Anatolievna Grishina, Anastasia Vladislavovna Ryabova, Mark Alekseevich Loskutnikov, Valeriy Valerevich Smirnov, Olga Dmitrievna Konova, Irina Andreevna Matsneva, Pavel Olegovich Bochkov
Introduction: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke. Patients and methods: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al...
2018: Pharmacogenomics and Personalized Medicine
Rong Hu, Daniel T Barratt, Janet K Coller, Benedetta C Sallustio, Andrew A Somogyi
Tacrolimus (TAC) is a first-line immunosuppressant used to prevent organ rejection after kidney transplantation. There is large inter-individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) in genes encoding TAC metabolising enzymes cytochromes P450 3A4/5 (CYP3A4/5), P-glycoprotein efflux transporter (ABCB1), their expression regulator pregnane X receptor (NR1I2), and CYP3A co-factor cytochrome P450 reductase (POR), have been studied for their effects on tacrolimus disposition...
March 30, 2018: Basic & Clinical Pharmacology & Toxicology
Bo Lindmark, Anna Lundahl, Kajsa P Kanebratt, Tommy B Andersson, Emre M Isin
BACKGROUND AND PURPOSE: Drugs metabolically eliminated by several enzymes are less vulnerable to variable compound exposure in patients due to drug-drug interactions (DDI) or if a polymorphic enzyme is involved in the elimination. Therefore, it is key in drug discovery to accurately and efficiently estimate and optimize the metabolic elimination profile. EXPERIMENTAL APPROACH: In this study, CYP3A and/or CYP2D6 substrates with well described variability in vivo in humans due to CYP3A DDI and CYP2D6 polymorphism were selected for assessment of fraction metabolized by each enzyme (fmCYP ) in two in vitro systems: A) human recombinant P450s (hrP450s) and B) human hepatocytes combined with selective P450 inhibitors...
March 25, 2018: British Journal of Pharmacology
Madelé van Dyk, Jean-Claude Marshall, Michael J Sorich, Linda S Wood, Andrew Rowland
PURPOSE: Cytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme. METHODS: This study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries...
March 23, 2018: European Journal of Clinical Pharmacology
Jingjing Yu, Zhu Zhou, Jessica Tay-Sontheimer, Rene H Levy, Isabelle Ragueneau-Majlessi
A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database and the clinical relevance of these observations was characterized based on information from New Drug Application reviews. CYP3A was identified as a major contributor to clinical drug-drug interactions (DDIs), involved in approximately 2/3 of all interactions. Transporters (alone or with enzymes) were found to participate in about half of all interactions, although most of these were weak-to-moderate interactions...
March 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Célia Lloret-Linares, Marija Bosilkovska, Youssef Daali, Marianne Gex-Fabry, Kyle Heron, Victor Bancila, Giorgio Michalopoulos, Nader Perroud, Hélène Richard-Lepouriel, Jean-Michel Aubry, Jules Desmeules, Marie Besson
OBJECTIVE: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach...
March 20, 2018: Journal of Clinical Psychiatry
Justin D Lutz, Brian J Kirby, Lu Wang, Qinghua Song, John Ling, Benedetta Massetto, Angela Worth, Brian P Kearney, Anita Mathias
Drug transporter and cytochrome P450 expression is regulated by shared nuclear receptors and hence, an inducer should induce both, though magnitude may differ. The objective of this study was to establish relative induction relationships between CYP3A and drug transporters (P-gp, OATP and BCRP) or other P450s (CYP2C9 and CYP1A2) using ascending doses of the prototypical PXR agonist, rifampin, to elicit weak, moderate and strong PXR agonism. Healthy subjects received dabigatran etexilate, pravastatin, rosuvastatin and a midazolam/tolbutamide/caffeine cocktail before and after rifampin 2, 10, 75, or 600 mg qd...
March 23, 2018: Clinical Pharmacology and Therapeutics
Justin D Lutz, Brian J Kirby, Lu Wang, Qinghua Song, John Ling, Benedetta Massetto, Angela Worth, Brian P Kearney, Anita Mathias
Rifampin demonstrated dose-dependent relative induction between CYP3A and P-gp, OATP or CYP2C9; P-gp, OATP and CYP2C9 induction was one DDI category lower than observed for CYP3A across a wide range of PXR agonism. The objective of this study was to determine if these relationships could be utilized to predict transporter induction by other CYP3A inducers (rifabutin and carbamazepine) and of another P-gp substrate, sofosbuvir. Healthy subjects received sofosbuvir and a six probe drug cassette before and after 300 mg qd rifabutin or 300 mg bid carbamazepine...
March 23, 2018: Clinical Pharmacology and Therapeutics
Rosa I Sanchez, Kerry L Fillgrove, Ka Lai Yee, Yuexia Liang, Bing Lu, Aditya Tatavarti, Rachael Liu, Matt S Anderson, Martin O Behm, Li Fan, Yun Li, Joan R Butterton, Marian Iwamoto, Sauzanne G Khalilieh
Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [14 C]doravirine (350 mg, ∼200 µCi) trial (N = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (N = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials...
March 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Jung Jae Jo, Jun Hyun Jo, SunJoo Kim, Jae-Mok Lee, Sangkyu Lee
Cocktail substrates are useful in investigating drug-drug interactions (DDI) that can rapidly identify the cytochrome P450 (CYP) isoforms that interact with test drugs. In this study, we developed and validated five probe drugs for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A using LC-MS/MS to determine CYP activities in mice. The five probe substrates were caffeine (2 mg/kg), bupropion (30 mg/kg), omeprazole (4 mg/kg), dextromethorphan (40 mg/kg), and midazolam (2 mg/kg) for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A, respectively...
March 17, 2018: Archives of Pharmacal Research
Wataru Ochiai, Hiroko Kobayashi, Satoshi Kitaoka, Mayumi Kashiwada, Yuya Koyama, Saho Nakaishi, Tomomi Nagai, Masaki Aburada, Kiyoshi Sugiyama
5,7-Dimethoxyflavone (5,7-DMF), one of the major components of Kaempferia parviflora, has anti-obesity, anti-inflammatory, and antineoplastic effects. On the other hand, in vitro studies have reported that it directly inhibits the drug metabolizing enzyme family cytochrome P450 (CYP) 3As. In this study, its safety was evaluated from a pharmacokinetic point of view, based on daily ingestion of 5,7-DMF. Midazolam, a substrate of CYP3As, was orally administered to mice treated with 5,7-DMF for 10 days, and its pharmacokinetic properties were investigated...
March 17, 2018: Journal of Natural Medicines
C M Chavez-Eng, R W Lutz, D Goykhman, K P Bateman
Methodology for analysis of a microdosing drug cocktail designed to evaluate the contribution of drug transporters and drug metabolizing enzymes to disposition was developed using LC-MS based detection. Fast and sensitive methods were developed and qualified for the quantification of statins (pitavastatin, pitavastain lactone, rosuvastatin, atorvastatin, 2-hydroxy, and 4-hydroxy atorvastatin), midazolam, and dabigatran in human plasma. Chromatographic separation was accomplished using reversed phase liquid chromatography or HILIC with gradient elution and detection by MS/MS in the positive ionization mode using electrospray ionization...
March 13, 2018: Journal of Pharmaceutical Sciences
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