Lauren A Marcath, Amy L Pasternak, Daniel L Hertz
Cytochrome P450 enzyme variant alleles have shown evidence that functional consequences differ between substrates. A systematic effort has not yet been made to confirm substrate-dependent activity. This review will discuss the challenges of assessing three examples (CYP2C8*3, CYP2D6*10, and CYP2C9*2) where substrate-dependent activity has been hypothesized with differing levels of evidence and their potential clinical implications. Data supports bidirectional substrate-dependent activity for CYP2C8*3. Although some data suggests CYP2D6*10 causes differences in the magnitude of effect across substrates, confirmatory studies are needed...
October 15, 2019: Pharmacogenomics Journal
Touraj Shokati, Marcel Hartmann, Baharak Davari, Jost Klawitter, Jelena Klawitter, Uwe Christians
1. Temsirolimus, a derivative of sirolimus, exhibits potent antitumor properties. It was the goal of this study to identify yet unknown temsirolimus metabolites generated after incubation with human liver microsomes. Previously, 23-hydroxy-, 24-hydroxy, 12-hydroxy, hydroxy-piperidine and 27-O-desmethyl temsirolimus had been described. 2. Metabolite strutures were identified using high-resolution mass spectrometry, MS/iontrap (MSn ) and comparison of fragmentation patterns of the metabolites with those of temsirolimus and other known sirolimus derivatives...
October 9, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
William R Arnold, Susan Zelasko, Daryl D Meling, Kimberly Sam, Aditi Das
Cytochrome P450 2C8 (CYP2C8) epoxygenase is responsible for the metabolism of over 60 clinically relevant drugs, notably the anticancer drug Taxol (paclitaxel, PAC). Specifically, there are naturally occurring polymorphisms, CYP2C8*2 and CYP2C8*3, that display altered PAC hydroxylation rates despite these mutations not being located in the active site. Herein, we demonstrate that these polymorphisms result in a greater uncoupling of PAC metabolism by increasing the amount of hydrogen peroxide formed per PAC turnover...
September 18, 2019: International Journal of Molecular Sciences
Hironobu Yagishita, Shinichiro Minami, Yumiko Akamine, Shotaro Kato, Katsunori Iijima, Masatomo Miura
WHAT IS KNOWN AND OBJECTIVE: Lenvatinib inhibits CYP2C8. (S)-Warfarin is metabolized to (S)-7-hydroxywarfarin by CYP2C9 and (S)-4'-hydroxywarfarin by CYP2C8. Here, we report drug interactions between warfarin and lenvatinib in a patient with CYP2C9*1/*3. CASE SUMMARY: The patient was administered warfarin. His international normalized ratio (INR) was 1.92 before lenvatinib administration. On day 8 after beginning 12 mg/day lenvatinib, plasma trough concentrations of lenvatinib and (S)-warfarin were 33...
August 30, 2019: Journal of Clinical Pharmacy and Therapeutics
Z Guo, W Cui, L Que, C Li, X Tang, J Liu
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication that can develop in patients treated with anti-resorptive drugs. Although the pathogenesis of MRONJ is still unclear, genetic factors have a demonstrated important role. Thus, the aim of this study was to perform a systematic review on the pharmacogenetics of MRONJ. Studies published until March 2019 were retrieved from eight databases and were selected by two independent reviewers. Evidence on several genetic polymorphisms was summarized and a meta-analysis was conducted when possible...
August 21, 2019: International Journal of Oral and Maxillofacial Surgery
Wilasinee Dunkoksung, Nontima Vardhanabhuti, Pongpun Siripong, Suree Jianmongkol
Rhinacanthin-C is a major active constituent in Rhinacanthus nasutus (L.) Kurz, a plant widely used in herbal remedies. Its potential for pharmacokinetic herb-drug interaction may exist with drug transporters and drug metabolizing enzymes. This study assessed the possibility for rhinacanthin-C-mediated drug interaction by determining its inhibitory effects against major human efflux and influx drug transporters as well as various human cytochrome P450(CYP) isoforms. Rhinacanthin-C demonstrated a moderate permeability through the Caco-2 monolayers [Papp (AP-to-BL) = 1...
October 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Roberta Natália Cestari, Adriana Rocha, Renê Donizeti Ribeiro de Oliveira, Vera Lucia Lanchote
Gemfibrozil (GFZ) is a derivative of fibric acid and is used in the treatment of dyslipidemia. GFZ may affect the metabolism of various drugs, including statins, by inhibiting the sinusoidal influx transporter OATP1B1 and also CYP2C9 and CYP2C8 enzymes. This study presents the development and validation of a rapid, simple, sensitive and reproducible method of GFZ analysis in human plasma using UPLC-MS/MS. The method was applied in a pharmacokinetic study following administration of multiple doses of 600 mg GFZ every 12 h in healthy volunteers (n = 15)...
July 8, 2019: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Meera Tugnait, Neeraj Gupta, Michael J Hanley, Daryl Sonnichsen, David Kerstein, David J Dorer, Karthik Venkatakrishnan, Narayana Narasimhan
In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2...
July 9, 2019: Clinical Pharmacology in Drug Development
Mariana R Botton, Xingwu Lu, Geping Zhao, Elena Repnikova, Yoshinori Seki, Andrea Gaedigk, Eric E Schadt, Lisa Edelmann, Stuart A Scott
The human CYP2C locus harbors the polymorphic CYP2C18, CYP2C19, CYP2C9 and CYP2C8 genes, and of these, CYP2C19 and CYP2C9 are directly involved in the metabolism of ~15% of all medications. All variant CYP2C19 and CYP2C9 star (*) allele haplotypes currently catalogued by the Pharmacogene Variation (PharmVar) Consortium are defined by sequence variants. To determine if structural variation also occurs at the CYP2C locus, the 10q23.33 region was interrogated across deidentified clinical chromosomal microarray (CMA) data from 20,642 patients tested at two academic medical centers...
July 1, 2019: Human Mutation
Xiaoyi Qi, Tongyi Dou, Zhongqiong Wang, Jianming Wu, Ling Yang, Su Zeng, Mingming Deng, Muhan Lü, Sicheng Liang
Compared with coumarin, 7-hydroxycoumarin could serve as a better hit for developing CYP2A6 inhibitors. In this study, a series of 7-hydroxycoumarin and its structural analogues were collected to study their structure-activity relationship (SAR) and isoform selectivity for inhibiting CYP2A6. All tested coumarins except a C4 phenyl derivative (11) showed higher inhibitory activities for CYP2A6 over the other CYP isoforms, including CYP1A2, CYP2D6, CYP2E1, CYP3A4, CYP2C8, and CYP2C9. Of these coumarins, 6,7-dihydroxycoumarin (1) and 7,8-dihydroxycoumarin (9) were found to be potent inhibitors of CYP2A6 with IC50 /Ki value of 0...
June 1, 2019: European Journal of Pharmaceutical Sciences
Clarissa Lourenço de Castro, Luiz Carlos da Costa Junior, Letícia Vieira Lourenço, Karine Souza Seba, Taiana Sousa Lopes da Silva, Rosane Vianna-Jorge
PURPOSE: Gynecologic malignancies are often detected in advanced stages, requiring chemotherapy with taxane/platinum combinations, which may cause severe toxicities, such as neutropenia and peripheral neuropathy. Gene polymorphisms are suspected as possible causes for the interindividual variability on chemotherapy toxicities. OBJECTIVE: To evaluate the role of ABCB1 1236C>T, 3435C>T; CYP2C8*3; CYP3A5*3C variants on paclitaxel/carboplatin toxicities. METHODS: A cohort of 503 gynecologic cancer patients treated with paclitaxel/carboplatin at the Brazilian National Cancer Institute (INCA-Brazil) was recruited (2013-2017)...
May 23, 2019: Archives of Gynecology and Obstetrics
Xueyan Zhou, Chunxia Chen, Di Yin, Feng Zhao, Zejun Bao, Yun Zhao, Xi Wang, Wei Li, Tao Wang, Yingliang Jin, Dongmei Lv, Qian Lu, Xiaoxing Yin
Background Previous studies have suggested that variations in the ABCC8 gene may be closely associated with T2DM susceptibility and repaglinide response. However, these results have not been entirely consistent, and there are no related studies in a Chinese population, suggesting the need for further exploration. Objective The current study investigated the associations of the ABCC8 rs1801261 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients...
May 22, 2019: Internal Medicine
Ahmed A Albassam, Reginald F Frye
Pterostilbene is a natural polyphenol compound found in small berries that is related to resveratrol, but has better bioavailability and a longer half-life. The purpose of this study was to assess the potential inhibitory effect of pterostilbene on in vitro drug metabolism. The effect of pterostilbene on cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzyme activities were studied using the enzyme-selective substrates amodiaquine (CYP2C8), midazolam (CYP3A4), estradiol (UGT1A1), serotonin (UGT1A6) and mycophenolic acid (UGT1A8/9/10)...
March 2019: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Elena Puris, Markku Pasanen, Veli-Pekka Ranta, Mikko Gynther, Aleksanteri Petsalo, Pirjo Käkelä, Ville Männistö, Jussi Pihlajamäki
There is a lack of information about the changes in drug pharmacokinetics and cytochrome P450 (CYP) metabolism after bariatric surgery. Here, we investigated the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery on pharmacokinetics of nine drugs given simultaneously which may reveal changes in the activities of the main CYPs. Eight obese subjects undergoing LRYGB received an oral cocktail containing nine drugs, substrates of various CYPs: melatonin (CYP1A2), nicotine (CYP2A6), bupropion (CYP2B6), repaglinide (CYP2C8), losartan (CYP2C9), omeprazole (CYP2C19/CYP3A4), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1), midazolam (CYP3A)...
March 27, 2019: Basic & Clinical Pharmacology & Toxicology
Nicola Melillo, Adam S Darwich, Paolo Magni, Amin Rostami-Hodjegan
Physiologically based pharmacokinetic (PBPK) models often include several sets of correlated parameters, such as organ volumes and blood flows. Because of recent advances in proteomics, it has been demonstrated that correlations are also present between abundances of drug-metabolising enzymes in the liver. As the focus of population PBPK has shifted the emphasis from the average individual to theoretically conceivable extremes, reliable estimation of the extreme cases has become paramount. We performed a simulation study to assess the impact of the correlation between the abundances of two enzymes on the pharmacokinetics of drugs that are substrate of both, under assumptions of presence or lack of such correlations...
March 23, 2019: Journal of Pharmacokinetics and Pharmacodynamics
Bin Xie, Yuan-Yuan Lu, Zhuo-Hui Luo, Zhao Qu, Chun-Ge Zheng, Xin-An Huang, Hong-Yan Zhou, Ying-Jie Hu, Xiao-Ling Shen
ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima (Roxb.) Wight et Arn is a vine distributed in southwest area of China and used in folk medicine for treatment of tumors. Recent decades of studies on this plant reveal its synergistic effects with certain anticancer drugs in cancer therapy. In our previous study, an extract ETA which contains total aglycones made from M. tenacissima significantly enhanced antitumor activity of paclitaxel in tumor-bearing mice. However, the effective constituents inETA and the underlying mechanisms remain unclear...
February 14, 2019: Journal of Ethnopharmacology
Guru R Valicherla, Amrut Mishra, Srinivas Lenkalapelly, Bhupathi Jillela, Femi M Francis, Lakshman Rajagopalan, Pratima Srivastava
1. A protocol has been developed and validated for the high throughput screening of eight major human cytochrome P450 (CYP) isozymes inhibition (CYP 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, 2C8 and 2E1) using an in vitro probe cocktail containing eight substrates by overcoming the unfavorable effect of assay conditions on CYP2E1 inhibition data. 2. The cocktail consisting of selective probe substrates like Tacrine (CYP1A2), Diclofenac (CYP2C9), S-Mephenytoin (CYP2C19), Dextromethorphan (CYP2D6), Midazolam (CYP3A4), Bupropion (CYP2B6), Paclitaxel (CYP2C8) and Chlorzoxazone (CYP2E1) was incubated with human liver microsomes...
February 12, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Shuang Zhou, Qian Xiang, Guangyan Mu, Lingyue Ma, Shuqing Chen, Qiufen Xie, Zhuo Zhang, Yimin Cui
OBJECTIVE: The purpose of this systematic review and meta-analysis was to summarize the potential impact of CYP2C8 and SLCO1B1 genetic polymorphisms on repaglinide pharmacokinetics. METHOD: A systematic search was conducted using electronic databases. Eligible studies reported data from pharmacokinetic evaluations of repaglinide in healthy adults according to different categories of CYP2C8 and SLCO1B1 genetic polymorphisms. RESULTS: Six studies including a total of 191 participants met the inclusion criteria...
January 10, 2019: Current Drug Metabolism
Matti K Itkonen, Aleksi Tornio, Mikko Neuvonen, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, a H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized cross-over study in eleven healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 mg, and 75 mg on 2 following days) with that of gemfibrozil (600 mg b...
January 10, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Weiyu Hao, Yanfeng Zhang, Yun Xie, Baoyuan Guo, Jing Chang, Jianzhong Li, Peng Xu, Huili Wang
Enantioselective toxicokinetics, accumulation, and toxicity of myclobutanil were investigated by oral exposure of myclobutanil enantiomers to lizards. After a single oral administration, the absorption half-lives ( [Formula: see text] ) and elimination half-lives (t1/2k ) were in the range of 0.133-14.828 and 3.641-17.682 h, respectively. The absorption and elimination half-lives of (+)-myclobutanil showed no significant differences from those of (-)-myclobutanil in lizard blood, whereas preferential enrichment of (-)-enantiomer was observed in the liver, fat, skin, intestine, lung and kidney...
January 3, 2019: Ecotoxicology and Environmental Safety
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