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Jingwei Zhang, Chuansheng Li, Jingfa Zhang, Fan Zhang
1. Sophocarpine is a biologically active component isolated from the foxtail-like sophora herb and seed that is often orally administered for the treatment of cancer and chronic bronchial asthma. However, whether sophocarpine affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. 2. In this study, the inhibitory effects of sophocarpine on the eight human liver CYP isoforms (CYP1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
April 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Ales Sorf, Jakub Hofman, Radim Kučera, Frantisek Staud, Martina Ceckova
Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP-binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development. With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transporter-mediated MDR using established in vitro methods...
April 16, 2018: Biochemical Pharmacology
Tae Yeon Kong, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Jin Young Kim, Hye Suk Lee
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS)...
April 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Abdoljalal Marjani, Aman Mohammad Gharanjik
Cytochrome P450 2C9 (CYP2C9) is involved in metabolism of many important drugs and its genotype variations is thought to affect drug efficacy and the treatment process. The aim of this study was to assess the distribution of CYP2C9 allele and genotypic variants in Sistani ethnic group, living in Gorgan, South East of Caspian Sea and North East of Iran. This study included 140 Sistani, referred to the health center of Gorgan. CYP2C9 genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism technique...
April 2018: Indian Journal of Clinical Biochemistry: IJCB
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
Kai Liao, Yong Liu, Chun-Zhi Ai, Xi Yu, Wei Li
OBJECTIVE: Therapeutic response to phenytoin (PHT), a first-line antiepileptic drug (AED), is highly variable, in part likely due to genetic factors. Genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C19 are expected to affect the metabolism of PHT and consequently affect its maintenance doses. We aimed to clarify the effects of genetic polymorphisms in both enzymes on daily PHT maintenance dosage in Asian epileptic patients by meta-analysis. MATERIALS AND METHODS: A systematic literature search was conducted in PubMed and EMBASE for relevant studies published prior to April 14, 2017...
April 9, 2018: International Journal of Clinical Pharmacology and Therapeutics
Ahmed M L Bedewy, Salah A Sheweita, Mostafa Hasan Mostafa, Lamia Saeed Kandil
[This corrects the article DOI: 10.1007/s12288-016-0725-4.].
April 2018: Indian Journal of Hematology & Blood Transfusion
Ahmed M L Bedewy, Salah Showeta, Mostafa Hasan Mostafa, Lamia Saeed Kandil
Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its effect by inhibition of vitamin K epoxide reductase...
April 2018: Indian Journal of Hematology & Blood Transfusion
Irina V Haidukevich, Tatsiana A Sushko, Anastasia M Tumilovich, Irina P Grabovec, Sergey A Usanov, Andrei A Gilep
CYP2C9 plays a major role in drug metabolism. It is highly polymorphic and among the variants, CYP2C9*2 and CYP2C9*3 have been known to encode the protein with moderately to markedly reduced catalytic activity. Azole antifungals are among the most frequently used drugs in human pharmacotherapy and represent a widely used class of pesticides to which humans are inevitably exposed. Due to the similarities in CYP organization throughout species, azoles can interact not only with the target fungal CYP51 substrate-binding site but can also modulate the catalytic activity of human cytochrome P450s, including CYP2C9, causing severe adverse effects...
April 2, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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
Young Jae Choi, Ji-Yoon Lee, Chang Seon Ryu, Yong Ha Chi, Soo Heui Paik, Sang Kyum Kim
Fimasartan (FMS), an angiotensin II receptor antagonist, is metabolized to FMS S-oxide, FMS N-glucuronide, oxidative desulfurized FMS (BR-A-557), and hydroxy-n-butyl FMSs. The purpose of this study was to characterize enzymes involved in NADPH-dependent FMS metabolism using recombinant enzymes such as cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), as well as selective chemical inhibitors. The results showed that CYP, but not FMO, plays a major role in FMS metabolism. CYP2C9, CYP3A4, and CYP3A5 were involved in the formation of FMS S-oxide, which was further metabolized to BR-A-557 by CYP3A4/5...
March 26, 2018: Food and Chemical Toxicology
Elena K Schneider
Since release of ivacaftor-lumacaftor several red-flags have been raised that highlight the clinical efficacy of this combination strategy may be be limited due to antagonistic drug-drug interactions. </p><p> Method: The effect of ivacaftor, its major metabolites M1 and M6, lumacaftor and the novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator tezacaftor at 10 µg/mL on the enzymatic activity of the major xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 as well as the minor enzymes CYP2B6 and CYP2C9 was assayed...
March 27, 2018: Drug Metabolism Letters
Yi-Er Qiu, Jun Qin, Yang Luo, Shao-Lan Qin, Yi-Fei Mu, Ran Cun, Hou-Li Jiang, Jian-Jun Chen, Min-Hao Yu, Ming Zhong
BACKGROUND: Previous preclinical evidence has suggested that the elevation of epoxyeicosatrienoic acids (EETs) derived from the cytochrome P450 (CYP) epoxygenases-dependent metabolism of arachidonic acid has important anti-inflammatory effects. However, the levels of EETs and their synthetic and metabolic enzymes in human ulcerative colitis has not been evaluated. METHOD: To evaluate EETs and the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), tissue biopsies were collected from 16 pairs of ulcerative colitis patients' tissues and matched with adjacent non-inflamed tissues...
March 23, 2018: Prostaglandins & Other Lipid Mediators
Lin-Hu Ye, Xin-Qian Zhao, Ling-Ti Kong, Li-Sha Wang, Xue Tao, Hui Wu, Mei He, Qi Chang
Danhong Injection (DHI),as a Chinese patent medicine, which is mainly used to treat ischemic encephalopathy and coronary heart disease in combination with other chemotherapy. However, the information on DHI that cause potential drug interaction is limited. The goal of this work was to examine the potential P450-mediated metabolism drug interaction arising by the DHI and its active components. The results showed that DHI inhibited CYP2C19, CYP2D6, CYP3A4, CYP2E1 and CYP2C9 with the IC50 values of 1.26%, 1.42%, 1...
March 26, 2018: Biomedical Chromatography: BMC
William L Marshall, Jacqueline B McCrea, Sreeraj Macha, Karsten Menzel, Fang Liu, Arne van Schanke, Joanna I Udo de Haes, Azra Hussaini, Heather R Jordan, Melissa Drexel, Bhavna S Kantesaria, Christine Tsai, Carolyn R Cho, Ellen G J Hulskotte, Joan R Butterton, Marian Iwamoto
Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age...
March 26, 2018: Journal of Clinical Pharmacology
María José Serna, José Miguel Rivera-Caravaca, Rocío Gonzalez-Conejero, María Asunción Esteve-Pastor, Mariano Valdés, Vicente Vicente, Gregory Y H Lip, Vanessa Roldán, Francisco Marín
BACKGROUND: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score. MATERIAL AND METHODS: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months...
March 25, 2018: European Journal of Clinical Investigation
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
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