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Guillermo Gervasini, Guadalupe García-Pino, Esther Vergara, Sonia Mota-Zamorano, Montserrat García-Cerrada, Enrique Luna
PURPOSE: We aimed to determine whether polymorphisms in CYP3A genes may affect the risk of acute rejection episodes (ARE) in renal transplant recipients treated with calcineurin inhibitors (CNIs). METHODS: One hundred and thirty seven patients and their respective donors were screened, by RT-PCR techniques, for three polymorphisms previously related with CNI pharmacokinetics and pharmacodynamics (CYP3A4*1B, CYP3A4*22 and CYP3A5*3). Genotypes of donors and recipients were associated by logistic regression models with ARE risk and exposure to CNIs...
October 18, 2017: European Journal of Clinical Pharmacology
Mohammad Mohajeri, Behzad Behnam, Arrigo F G Cicero, Amirhossein Sahebkar
Aflatoxicosis is a deleterious medical condition that results from aflatoxins (AFs) or ochratoxins (OTs). Contamination with these toxins exerts detrimental effects on the liver, kidneys, reproductive organs, and also on immunological and cardiovascular systems. Aflatoxicosis is closely associated with overproduction of reactive oxygen species (ROS) as key contributors to oxidative and nitrosative stress responses, and subsequent damages to lipids, proteins, RNA, and DNA. The main target organ for AF toxicity is the liver, where DNA adducts, degranulation of endoplasmic reticulum, increased hepatic lipid peroxide, GSH depletion, mitochondrial dysfunction, and reduction of enzymatic and non-enzymatic antioxidants are manifestations of aflatoxicosis...
October 16, 2017: Journal of Cellular Physiology
Bokyeong Ryu, C-Yoon Kim, Hanseul Oh, Ukjin Kim, Jin Kim, Cho-Rok Jung, Byoung-Hee Lee, Seungki Lee, Seo-Na Chang, Ji Min Lee, Hyung-Min Chung, Jae-Hak Park
An evaluation of intestinal toxicity is important because the mucosal lining of the gastrointestinal tract is the first barrier for oral xenobiotics. Until now, a rat model has been recommended as the standard intestinal toxicity model and the Caco-2 cell line, originated from a human colon adenocarcinoma, has been used as an alternative to this model, but there are limitations regarding cost-effectiveness and the need for mimicry of the human system. In this study, we investigated whether zebrafish could be a valid alternative to rats and Caco-2 cells as an intestinal toxicity model...
October 13, 2017: Journal of Applied Toxicology: JAT
Hui Wang, Ying Peng, Tingjian Zhang, Qunsheng Lan, Huimin Zhao, Wenbao Wang, Yufei Zhao, Xu Wang, Jianxin Pang, Shaojie Wang, Jiang Zheng
Benzbromarone (BBR) is effective in the treatment of gout but can also cause fatal hepatic failure in clinic. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) which reacted with sulfur nucleophiles of protein to form protein covalent binding both in vitro and in vivo. The present study attempted to define the correlation between metabolic epoxidation and hepatotoxicity of BBR by manipulating the structure of BBR. We rationally designed and synthesized three halogenated BBR derivatives (6-F-, Cl-, or Br-BBR) to decrease the potential for P450-mediated metabolic activation...
October 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Nicholas A Keks, Judy Hope, Simone Keogh
OBJECTIVE: Suvorexant, a new hypnotic, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance, and is used long-term. This paper will briefly review suvorexant. RESULTS: Orexin is a hypothalamic peptide which promotes wakefulness. By blocking orexin receptors, suvorexant induces sleep. Peaking 2 h after ingestion, it has a half-life of 12 h and is hepatically metabolized mainly by CYP3A. Kinetics are not affected by age but concentrations are higher in females and obese patients...
October 1, 2017: Australasian Psychiatry: Bulletin of Royal Australian and New Zealand College of Psychiatrists
M Neary, A Owen
Variations in the human genome sequence sometimes play an important role in pharmacokinetics and/or pharmacodynamics. Previous studies have demonstrated a high degree of variation both between and within different ethnic populations. Areas Covered: This review sought to summarise key SNPs in CYP2B6, CYP3A enzymes, CYP2C enzymes, UGT2 enzymes, ABCB1, ABCC2, SLCO1B1, NR1I2 and NR1I3 that have previously been associated with variability in antiretroviral pharmacokinetics. Additionally, the impact of ethnicity in these pharmacogenetics studies is discussed and variation in findings between different ethnic groups is reviewed...
October 10, 2017: Expert Opinion on Drug Metabolism & Toxicology
Arian Emami Riedmaier, David J Lindley, Jeffrey A Hall, Steven Castleberry, Russell T Slade, Patricia Stuart, Robert A Carr, Thomas B Borchardt, Daniel A J Bow, Marjoleen Nijsen
PURPOSE: Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system (BCS) class IV compound. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion (ASD) formulation of venetoclax in humans. METHODS: A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism and plasma protein binding...
October 6, 2017: Journal of Pharmaceutical Sciences
Xin Wang, Zhou Qiao, Jia Liu, Mei Zheng, Wenyuan Liu, Chunyong Wu
1. The objective was to investigate the underlying mechanism of the stereoselectivity in the metabolism of rhynchophylline (RIN) and isorhynchophylline (IRN) epimers in rat liver microsomes (RLM). 2. After incubation, eight metabolites of RIN (M1-5) and IRN (M6-8) reacted at A- and C-ring were identified using LC-Q-TOF/MS. Metabolic pathways included oxidation, hydroxylation, N-oxidation and dehydrogenation. In addition, hydroxylation at A-ring were the major metabolic pathway for RIN whereas the oxidation at C-ring was the major one for IRN...
October 9, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Suresh Palle, Prasad Neerati
1. Quercetin is a dietary flavonoid has extremely low water solubility and found to possess CYP3A inhibitory activity. The purpose of the present study was to evaluate the effect of quercetin and quercetin nanoparticles (NQC) on the pharmacokinetics of bromocriptine (BRO) in rats. 2. NQC prepared by antisolvent precipitation method and characterized by SEM and dissolution test. The following methods were used in this study i.e. in vitro liver and intestinal CYP3A microsomal activity and in vitro non-everted sac method...
October 9, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Nan Zhang, Jihong Shon, Myong-Jin Kim, Chongwoo Yu, Lei Zhang, Shiew-Mei Huang, LaiMing Lee, Doanh Tran, Li Li
No abstract text is available yet for this article.
October 6, 2017: Clinical and Translational Science
Xuan Zhou, Yang-Yang Gao, Jian-Yong Hu, Yu Dong, Hai-Zhu Zhang, Yong Lai
OBJECTIVE: The purpose of this study was to investigate the influence of breviscapine on the pharmacokinetics of concomitantly administered midazolam (MID) and its associations with and effects on genetic polymorphism of the gene encoding cytochrome P450 3A5 (CYP3A5) in healthy volunteers. METHODS: The study group comprised 17 healthy volunteers who had been genotyped for CYP3A5*3 prior to start of the study. These volunteers were given daily doses of 120 mg (40 mg, three times a day) of breviscapine or a placebo for 14 days, followed by 7...
October 6, 2017: European Journal of Clinical Pharmacology
Sylvie E Kandel, Lyrialle W Han, Qingcheng Mao, Jed N Lampe
The metabolism of testosterone to 6β-hydroxytestosterone is a commonly used assay to evaluate human CYP3A enzyme activities. However, previous reports have indicated that CYP3A7 also produces 2α-hydroxytestosterone, and that a 2α-hydroxytestosterone:6β-hydroxytestosterone ratio may be a unique biomarker of the isozyme's activity. Until now, the full metabolite and kinetic profile for testosterone hydroxylation by CYP3A7 has not been fully examined. To this end, we performed a complete kinetic analysis of the 6β-hydroxytestosterone, 2α-hydroxytestosterone and 2β-hydroxytestosterone metabolites for recombinant SupersomeTM CYP3A4, 3A5, and 3A7 enzymes and monitored metabolism in fetal and adult human liver microsomes for comparison...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Xiaoyun Liu, Yifan Zhang, Qian Chen, Yan Zhan, Quanren Wang, Chaoying Hu, Chen Yu, Zitao Guo, Xiaoyan Chen, Dafang Zhong
Apatinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with advanced-stage gastric cancer or gastroesophageal junction cancer who have progressed or recurred after at least 2 kinds of systemic chemotherapy. In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of apatinib. Pharmacokinetic drug-drug interactions of apatinib and (1) a CYP3A4 inducer (rifampin) or (2) a CYP3A inhibitor (itraconazole) were clinically evaluated in healthy volunteers...
October 2, 2017: Journal of Clinical Pharmacology
Niloufar Marsousi, Jules A Desmeules, Serge Rudaz, Youssef Daali
In recent years, Physiologically-Based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for assessment of drug PK. It has demonstrated to be informative and helpful to quantify the modification in drug exposure due to specific physio-pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug-drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism-based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism-based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software...
September 28, 2017: Biopharmaceutics & Drug Disposition
Md Amin Hossain, Timothy Tran, Tianmeng Chen, Gerd Mikus, David J Greenblatt
OBJECTIVES: Ritonavir and cobicistat are strong inhibitors of human cytochrome P450-3A (CYP3A) isoforms, and are used clinically as pharmacokinetic boosting agents for other antiretroviral drugs. Data reported by the manufacturer suggest that cobicistat is a more selective inhibitor of CYP3A than ritonavir. However, this claim has not been validated in clinical studies. This study evaluated the in-vitro inhibitory potency of ritonavir and cobicistat vs a series of human CYP isoforms. METHOD: The model system utilized human liver microsomes and isoform-selective index substrates...
September 29, 2017: Journal of Pharmacy and Pharmacology
Annika Wahlström, Samer Al-Dury, Marcus Ståhlman, Fredrik Bäckhed, Hanns-Ulrich Marschall
Humans and mice differ substantially in their bile acid profiles as mice in addition to cholic acid (CA) predominantly synthesize 6β-hydroxylated muricholic acids (MCAs) whereas humans produces chenodeoxycholic acid (CDCA) and CA as primary bile acids. Identifying the gene performing 6β-hydroxylation would be useful for 'humanizing' the bile acid profile in mice for studies of the interaction between bile acids, gut microbiota, and host metabolism. We investigated the formation of MCAs in primary murine hepatocytes and found that αMCA is synthesized from CDCA and βMCA from UDCA...
July 2017: Biochemistry and Biophysics Reports
Sarah Maximos, Michel Chamoun, Sophie Gravel, Jacques Turgeon, Veronique Michaud
Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The cyp450 mRNA expression levels for 15 different isoforms were determined in the liver and extra-hepatic tissues (kidneys, lungs and heart) of HFD-treated animals (n = 45). Modulation of cyp450 metabolic activities by HFD was assessed using eight known substrates for specific human ortholog CYP450 isoforms: in vitro incubations were conducted with liver and extra-hepatic microsomes...
September 26, 2017: Pharmaceutics
Bo Sun, Yankun Guo, Junwei Gao, Weifeng Shi, Guorong Fan, Xiaoyu Li, Jianxin Qiu, Yan Qin, Gaolin Liu
AIM: Cyclosporine is a substrate of CYP3A and ABCB1. This study examined the role of CYP3A and ABCB1 polymorphisms on cyclosporine pharmacokinetics in renal transplant recipients. PATIENTS & METHODS: CYP3A and ABCB1 SNPs were detected in 521 recipients. The relationships of dose-adjusted concentrations with corresponding genotypes were investigated at the different terms. RESULTS: CYP3A5 rs776746 and CYP3A7 rs10211 genotype affect C0/D at the short-term, medium-term and long-term after transplantation (p < 0...
September 27, 2017: Pharmacogenomics
Huan-Hua Xu, Mei-Xi Wang, Hong-Ling Tan, Yu-Guang Wang, Xiang-Lin Tang, Cheng-Rong Xiao, Hua Li, Yue Gao, Zeng-Chun Ma
To investigate the effect of clinical dose of Realgar-Indigo Naturais formula (RIF) and large-dose of Realgar on main drug-metabolizing enzymes CYP450s of rat liver, as well as its regulatory effect on mRNA expression. Wistar rats were administrated orally with tested drugs for 14 days. A Cocktail method combined with HPLC-MS/MS was used in the determination of 4 cytochrome P450 isozymes (CYP1A2, CYP2B, CYP3A and CYP2C) in liver of the rats, and the mRNA expression levels of the above subtypes were detected by real-time fluorescent quantitative PCR...
February 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Sara K Quinney, Tara Benjamin, Xiaomei Zheng, Avinash S Patil
INTRODUCTION: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. MATERIALS AND METHODS: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis-Menten equation to determine Km and Vmax...
September 26, 2017: Fetal and Pediatric Pathology
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