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Niloufar Marsousi, Youssef Daali, Pierre Fontana, Jean-Luc Reny, Virginie Ancrenaz-Sirot, Alexandra Calmy, Serge Rudaz, Jules Alexandre Desmeules, Caroline Flora Samer
BACKGROUND AND OBJECTIVES: Prasugrel and clopidogrel are inhibitors of the ADP-P 2 Y 12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. METHODS: In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial...
February 16, 2018: Clinical Pharmacokinetics
Geik Yong Ang, Choo Yee Yu, Richard Johari James, Aminuddin Ahmad, Thuhairah Abdul Rahman, Fadzilah Mohd Nor, Syahrul Azlin Shaari, Adzrool Idzwan Ismail, Lay Kek Teh, Mohd Zaki Salleh
CYP3A5 is the predominant subfamily of biotransformation enzymes in the liver and the genetic variations in CYP3A5 are an important determinant of interindividual and interethnic differences in CYP3A-mediated drug disposition and response. This study aims to investigate the genetic polymorphisms of CYP3A5 among the Orang Asli in Peninsular Malaysia using next generation sequencing platform. Genomic DNAs were extracted from blood samples of the three main Orang Asli tribes and whole-genome sequencing was performed...
February 15, 2018: Annals of Human Biology
Sophie Gravel, Jean-Louis Chiasson, Suzanne Dallaire, Jacques Turgeon, Veronique Michaud
INTRODUCTION: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response...
February 8, 2018: BMJ Open
Dwaipayan Mukherjee, Jiuhong Zha, Rajeev M Menon, Mohamad Shebley
Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously...
February 9, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Ying Zhang, Lan Miao, Li Lin, Chang-Ying Ren, Jian-Xun Liu, Yi-Min Cui
BACKGROUND: Sailuotong (SLT) is a standard Chinese preparation made from extracts of Panax ginseng (ginseng), Ginkgo biloba (ginkgo), and Crocus sativus (saffron). Preliminary clinical trials and animal experiments have demonstrated that SLT could improve cognition of vascular dementia (VD). PURPOSE: To avoid incident drug-drug interaction which is easily encountered in patients of VD, the potential influence of SLT on main drug-metabolic cytochromes P450 enzymes (CYP450) was investigated...
January 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Corinne Haines, Lynsey R Chatham, Audrey Vardy, Clifford R Elcombe, John R Foster, Brian G Lake
1. The hepatic and thyroid gland effects of the constitutive androstane receptor (CAR) activator sodium phenobarbital (NaPB) and the pregnane X receptor (PXR) activator pregnenolone-16α-carbonitrile (PCN) were examined in male Sprague-Dawley wild type (WT) and knockout (KO) rats lacking both hepatic CAR and PXR receptors (CAR KO/PXR KO rats). 2. The treatment of WT rats for 7 days with 500 ppm NaPB in the diet and 100 mg/kg/day PCN by gavage resulted in increased relative liver weight, hepatocyte hypertrophy, increased hepatocyte replicative DNA synthesis (RDS) and induction of cytochrome P450 CYP2B and CYP3A subfamily enzymes...
February 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Satoshi Kitaoka, Jo Hatogai, Ryuki Iimura, Yuka Yamamoto, Konomi Oba, Mami Nakai, Yoshiki Kusunoki, Wataru Ochiai, Kiyoshi Sugiyama
The use of midazolam in early stages of pregnancy has resulted in a high incidence of birth defects; however, the underlying reason is unknown. We investigated expression changes of the CYP3A molecular species and focused on its midazolam metabolizing activity from the foetal period to adulthood. CYP3A16 was the only CYP3A species found to be expressed in the liver during the foetal period. However, CYP3A11 is upregulated in adult mice, but has been found to be downregulated during the foetal period and to gradually increase after birth...
2018: Journal of Toxicological Sciences
Masahiro Iwaki, Toshiro Niwa, Yukiko Nakamura, Atsushi Kawase, Hiroshi Komura
The relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation in rats were evaluated in order to compare with that of reported human CYPs responsible for the metabolism of CAR enantiomers. The depletion of CAR enantiomers by recombinant CYPs and the effects of CYP-selective inhibitors on the depletion catalyzed by rat liver microsomes (RLM) was determined. Quinine (rat CYP2D inhibitor) markedly inhibited the metabolism of both R- and S-CAR by RLM. The metabolism of S-CAR was inhibited more than that of R-CAR by furafylline, (a CYP1A2 inhibitor, 53...
2018: Journal of Toxicological Sciences
Yan Xin, Winnie Weng, Bernard P Murray, Eugene J Eisenberg, Jason W Chien, John Ling, Jeffrey A Silverman
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5...
February 7, 2018: Journal of Clinical Pharmacology
Jin-Fu Yang, Yue-Rong Liu, Chiung-Chiao Huang, Yune-Fang Ueng
Hypericum perforatum [St. John's wort (SJW)] is known to cause a drug interaction with the substrates of cytochrome P450 (P450, CYP) isoforms, mainly CYP3A. This study aims to determine the dose response and time course of the effects of SJW extract on P450s, UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), and NAD(P)H-quinone oxidoreductase (NQO) in mice. The oral administration of SJW extract to male mice at 0.6 g/kg/d for 21 days increased hepatic oxidation activity toward a Cyp3a substrate nifedipine...
January 2018: Journal of Food and Drug Analysis
G E Benoist, M J van der Doelen, R Ter Heine, N P van Erp, N Mehra
ADVERSE EVENT: Decreased abiraterone exposure after introducing carbamazepine DRUGS IMPLICATED: Abiraterone acetate and carbamazepine THE PATIENT: A 65-year-old man with metastatic castration resistant prostate cancer, was treated with abiraterone acetate and prednisolone, and received concomitant carbamazepine for treatment of facial neuropathy EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The interaction was confirmed by a decrease in abiraterone exposure > 2-fold (area-under-the-curve and trough levels)...
January 31, 2018: British Journal of Clinical Pharmacology
Xiao Zhang, Taotao Zhang, Jing Liu, Muzi Li, Yong Fu, Jianhai Xu, Qun Liu
The basic metabolic cytochrome P450 (CYP) proteins are essential for the biotransformation of sterols and xenobiotics. By contrast, the Toxoplasma gondii genome contains only one CYP gene, and the role of this enzyme in the physiology and biochemistry of apicomplexan parasites is unknown. Because it is a potential resistance gene, identifying the functionality of P450 in T. gondii is particularly important. Knocking out Tg-P450 had no significant effect on T. gondii survival, but mice infected with parasites overexpressing Tg-P450 exhibited significantly enhanced pathogenicity...
December 29, 2017: Oncotarget
Karthick Vishwanathan, Paul A Dickinson, Karen So, Karen Thomas, Yuh-Min Chen, Javier De Castro Carpeño, Anne-Marie C Dingemans, Hye Ryun Kim, Joo-Hang Kim, Matthew G Krebs, James Chih-Hsin Yang, Khanh Bui, Doris Weilert, R Donald Harvey
AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two phase I, open-label, two-part clinical studies. Part one of both studies is reported. METHODS: In the itraconazole study (NCT02157883), patients received single-dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6-18 orally...
January 30, 2018: British Journal of Clinical Pharmacology
(no author information available yet)
OBJECTIVES: Carbamazepine and quetiapine are drugs that are used as mood stabilizers in the treatment of bipolar disorders. A series of studies has shown that concurrent use of carbamazepine decreases quetiapine serum level due to induction of CYP3A enzymes by carbamazepine. METHODS: In a 30-year-old bipolar patient with mania treated with quetiapine 1200 mg and carbamazepine 900 mg per day, we measured quetiapine serum level before and after carbamazepine withdrawal...
December 25, 2017: Neuro Endocrinology Letters
Ryuta Asaumi, Kota Toshimoto, Yoshifusa Tobe, Kenta Hashizume, Ken-Ichi Nunoya, Haruo Imawaka, Wooin Lee, Yuichi Sugiyama
This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of rifampicin that can accurately and quantitatively predict complex drug-drug interactions (DDIs) involving its saturable hepatic uptake and auto-induction. Using in silico and in vitro parameters, and reported clinical pharmacokinetic data, rifampicin PBPK model was built and relevant parameters for saturable hepatic uptake and UDP-glucuronosyltransferase auto-induction were optimized by fitting. The parameters for cytochrome P450 (CYP) 3A and CYP2C9 induction by rifampicin were similarly optimized using clinical DDI data with midazolam and tolbutamide as probe substrates, respectively...
January 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
Tsuyoshi Karibe, Tomoki Imaoka, Koji Abe, Osamu Ando
To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selectiveBCRP inhibition, in addition to several well-known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole...
January 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Akira Ogasawara, Nozomu Kato, Nao Torimoto, Fumika Aohara, Rikiya Ohashi, Yasuhiro Yamada, Hideki Taniguchi
BACKGROUND: The HepaRG cells have key drug metabolism functionalities comparable to those of primary human hepatocytes. Many studies have reported that this cell line can be used as a reliable in vitro model for human drug metabolism studies, including the assessment of cytochrome P450 (CYP) induction. OBJECTIVES: The objective of this study is to determine whether CYP mRNA level measurement is superior to the CYP enzyme activity measurement as a convenient high-throughput method for evaluating CYP induction potential using HepaRG cells...
January 18, 2018: Drug Metabolism Letters
Mohd Yusmaidie Aziz, Kurt-Jürgen Hoffmann, Michael Ashton
The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by LC-MS/MS as the rate of 1'-hydroxymidazolam formation. Piperaquine was found to be a reversible, potent inhibitor of CYP3A with the following parameter estimates (%CV): IC50 = 0.76 μM (29), Ki = 0.68 μM (29). In addition, piperaquine acted as a time-dependent inhibitor (TDI) with IC50 declining to 0.32 μM (28) during 30 min pre-incubation. TDI estimates were kinact = 0...
January 15, 2018: Journal of Pharmaceutical Sciences
Xia Li, Xiaojing Yang, E Xiang, Jinyuan Luo, Shuaikai Qiu, Yan Fang, Li Zhang, Yu Guo, Jiang Zheng, Hui Wang
Pyrrolizidine alkaloids (PAs) are extensively synthesized by plants and are commonly present in herbs and foodstuffs, which exhibit hepatotoxicity requiring metabolic activation by cytochrome P450 (CYP) 3A to form the electrophilic metabolites-pyrrolic ester. PAs also cause embryo toxicity, but the metabolic profiles of PAs in fetus and placenta have been far from clear. In this study, we determined the basal metabolic activation of retrorsine (RTS) in rat maternal liver, placenta and fetal liver in vitro, and examined the fetal toxicity and bioactivation of RTS in vivo...
January 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Dmitriy Alexeyevich Sychev, Arshak Vardanyan, Aleksandr Rozhkov, Edita Hachatryan, Ani Badanyan, Valery Smirnov, Anna Ananichuk, Natalya Denisenko
BACKGROUND: Rivaroxaban is metabolized in the liver via CYP3A4, the cytochrome involved in the metabolism of nearly 50% of all medications. Thus, its effective concentration depends on multiple pharmacologic parameters. METHODS: The primary goal of our research was to study the correlation between the CYP3A family activity and the safety and efficacy of anticoagulant therapy with rivaroxaban in patients with deep vein thrombosis (DVT). Thirty one patients with DVT aged 21-83 years, 18 men and 13 women, received rivaroxaban (Xarelto) 30 mg/day for 21 days after diagnosis and 20 mg/day for the follow-up period of 6 months...
January 2018: Genetic Testing and Molecular Biomarkers
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