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Allison B Chambliss, Molly Resnick, Athena K Petrides, William A Clarke, Mark A Marzinke
BACKGROUND: Current methods for the detection of single nucleotide polymorphisms (SNPs) associated with aberrant drug-metabolizing enzyme function are hindered by long turnaround times and specialized techniques and instrumentation. In this study, we describe the development and validation of a high-resolution melting (HRM) curve assay for the rapid screening of variant genotypes for targeted genetic polymorphisms in the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A5. METHODS: Sequence-specific primers were custom-designed to flank nine SNPs within the genetic regions of aforementioned drug metabolizing enzymes...
October 12, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
Ayumi Asada, Shigeki Bamba, Yukihiro Morita, Kenichiro Takahashi, Hirotsugu Imaeda, Atsushi Nishida, Osamu Inatomi, Mitsushige Sugimoto, Masaya Sasaki, Akira Andoh
BACKGROUND: Tacrolimus is an immunosuppressive agent, used in the remission induction therapy of ulcerative colitis (UC). AIMS: We investigated the correlation between CYP3A5 genetic polymorphisms and the adverse events in patients with UC. The pharmacokinetics of tacrolimus after oral administration were also analyzed. METHODS: We enrolled 29 hospitalized patients with UC received oral tacrolimus. Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan(®) SNP genotyping assays...
September 21, 2016: Digestive and Liver Disease
XiaoMei Zhuang, TianHong Zhang, SiJia Yue, Juan Wang, Huan Luo, YunXia Zhang, Zheng Li, JinJing Che, HaiYing Yang, Hua Li, MingShe Zhu, Chuang Lu
Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4...
September 22, 2016: Biochemical Pharmacology
Yin-Qing Wang, Chun-Hua Wang, Jin-Hua Zhang
INTRODUCTION: We wished to explore the relationship between CYP3A5 polymorphisms and adverse events in patients undergoing clopidogrel therapy. METHODS: A Boolean search of the PubMed, EMbase, OVID and Cochrane Library databases was conducted in April 2016. The primary outcome was major adverse cardiovascular events (MACE). The secondary outcome was bleeding events and resistance to the effects of clopidogrel. The CYP3A5 polymorphism was classified into three types: wild-type (AA), heterozygote (AG) and homozygous mutant (GG)...
September 17, 2016: Thrombosis Research
Katalin Tóth, Gábor Csukly, Dávid Sirok, Ales Belic, Ádám Kiss, Edit Háfra, Máté Déri, Ádám Menus, István Bitter, Katalin Monostory
BACKGROUND: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors. METHODS: Since the prominent role in clonazepam nitro-reduction and acetylation of 7-amino-clonazepam is assigned to CYP3A and N-acetyl transferase 2 enzymes, respectively, the association between the patients' CYP3A status (CYP3A5 genotype, CYP3A4 expression) or N-acetyl transferase 2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders...
October 3, 2016: International Journal of Neuropsychopharmacology
Xingyang Yi, Zhao Han, Qiang Zhou, Wen Cheng, Jing Lin, Chun Wang
OBJECTIVE: Conflicting data exist as to whether proton-pump inhibitors (PPIs) diminish the efficacy of clopidogrel. The aim of this study was to investigate the association between cytochrome P450 (CYP) genetic variants and clinical adverse outcomes of concomitant use of PPIs and clopidogrel by patients. METHODS: We consecutively enrolled 523 patients with ischemic stroke receiving clopidogrel. Platelet aggregation was measured before and after 7 to 10 days of clopidogrel treatment...
September 16, 2016: Clinical and Applied Thrombosis/hemostasis
Clint Mizzi, Eleni Dalabira, Judit Kumuthini, Nduna Dzimiri, Istvan Balogh, Nazli Başak, Ruwen Böhm, Joseph Borg, Paola Borgiani, Nada Bozina, Henrike Bruckmueller, Beata Burzynska, Angel Carracedo, Ingolf Cascorbi, Constantinos Deltas, Vita Dolzan, Anthony Fenech, Godfrey Grech, Vytautas Kasiulevicius, Ľudevít Kádaši, Vaidutis Kučinskas, Elza Khusnutdinova, Yiannis L Loukas, Milan Macek, Halyna Makukh, Ron Mathijssen, Konstantinos Mitropoulos, Christina Mitropoulou, Giuseppe Novelli, Ioanna Papantoni, Sonja Pavlovic, Giuseppe Saglio, Jadranka Setric, Maja Stojiljkovic, Andrew P Stubbs, Alessio Squassina, Maria Torres, Marek Turnovec, Ron H van Schaik, Konstantinos Voskarides, Salma M Wakil, Anneke Werk, Maria Del Zompo, Branka Zukic, Theodora Katsila, Ming Ta Michael Lee, Alison Motsinger-Rief, Howard L Mc Leod, Peter J van der Spek, George P Patrinos
Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes...
2016: PloS One
Evelien J M Kuip, Maarten L Zandvliet, Stijn L W Koolen, Ron H J Mathijssen, Carin C D van der Rijt
Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer-related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter- and intra-patient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way...
September 12, 2016: British Journal of Clinical Pharmacology
Yoshitaka Zenke, Shigeki Umemura, Eri Sugiyama, Keisuke Kirita, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Hironobu Ohmatsu, Koichi Goto
Hepatotoxicity is a major cause of the withdrawal of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) when treating EGFR mutation-positive non-small cell lung cancer (NSCLC). We report a case in which gefitinib- and elrotinib-induced severe hepatotoxicity arose in a patient with the uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) and cytochrome p450 3A5 (CYP3A5) poor metabolizer phenotypes. Afatinib is not significantly metabolized by cytochrome p450-mediated pathways...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Kazuyuki Numakura, Norihiko Tsuchiya, Hideaki Kagaya, Makoto Takahashi, Hiroshi Tsuruta, Takamitsu Inoue, Shintaro Narita, Mingguo Huang, Shigeru Satoh, Takenori Niioka, Masatomo Miura, Tomonori Habuchi
Although sunitinib is a well-established chemotherapeutic for metastatic renal cell carcinoma (mRCC), there are no robust markers that predict efficacy and toxicity. We analyzed the effect of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics on clinical outcomes in Japanese patients with mRCC. We analyzed the effect of SNPs in genes involved in sunitinib pharmacokinetics on the clinical outcome in mRCC patients in a Japanese population. We evaluated seven SNPs in four candidate genes, the transport proteins ATP-binding cassette (ABC) B1 (rs1045642, rs1128503, rs2032582, and rs7779562) and ABCG2 (rs2231142), and the metabolic proteins cytochrome P450 (CYP) 3A4 (rs35599367) and CYP3A5 (rs776746) in 70 patients...
August 25, 2016: Anti-cancer Drugs
Qian-Jie Tang, Hao-Ming Lin, Guo-Dong He, Ju-E Liu, Hong Wu, Xin-Xin Li, Wan-Ping Zhong, Lan Tang, Jin-Xiu Meng, Meng-Zhen Zhang, Han-Ping Li, Ji-Yan Chen, Shi-Long Zhong, Lai-You Wang
AIM: To investigate whether plasma miRNAs targeting CYP3A4/5 have an impact on the variance of pharmacokinetics of clopidogrel. MATERIALS & METHODS: The contribution of 13 miRNAs to the CYP3A4/5 gene expression and activity was investigated in 55 liver tissues. The association between plasma miRNAs targeting CYP3A4/5 mRNA and clopidogrel pharmacokinetics was analyzed in 31 patients with coronary heart disease who received 300 mg loading dose of clopidogrel. RESULTS: Among 13 miRNAs, miR-142 was accounting for 12...
September 2016: Pharmacogenomics
Xingyang Yi, Qiang Zhou, Chun Wang, Jing Lin, Wen Cheng, Lifen Chi
BACKGROUND AND PURPOSE: Conflicting data exist as to whether proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel. We, therefore, assessed the effect of concomitant PPI use in ischemic stroke (IS) patients receiving clopidogrel. METHODS: We consecutively enrolled 535 IS patients receiving clopidogrel, 166 of whom were concomitantly taking PPIs. Platelet aggregation was measured before and after 7-10 days of treatment with clopidogrel. Single nucleotide polymorphisms of CYP3A4, CYP3A5, CYP2C19*2, and CYP2C19*3 were examined...
August 18, 2016: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
Vikram Gota, Girish Chinnaswamy, Tushar Vora, Sanhita Rath, Akanksha Yadav, Murari Gurjar, Gareth Veal, Purna Kurkure
PURPOSE: To compare the pharmacokinetics of 13-cis retinoic acid (13-cisRA) between Indian and UK neuroblastoma patients receiving comparable treatment, alongside measures of toxicity and response. METHODS: 13-cisRA (160 mg/m(2)/day) was administered to 36 patients ≤16 years in two divided doses. Plasma 13-cisRA concentrations were determined on days 1 and 14 of cycles 1 and 4 of treatment. Area under the plasma concentration-time curve (AUC0-6h) was estimated using non-compartment modelling...
October 2016: Cancer Chemotherapy and Pharmacology
Wanaporn Charoenchokthavee, Duangchit Panomvana, Virote Sriuranpong, Nutthada Areepium
BACKGROUND: Tamoxifen (TAM) is used in breast cancer treatment, but interindividual variabilities in TAM-metabolizing enzymes exist and have been linked to single nucleotide polymorphisms in the respective encoding genes. The different alleles and genotypes of these genes have been presented for Caucasians and Asians. This study aimed to explore the prevalence of the incomplete functional alleles and genotypes of the CYP2D6 and CYP3A5 genes in Thai breast cancer patients undergoing TAM treatment...
2016: Breast Cancer: Targets and Therapy
Chun-Ting Lee, Jia Chen, Abigail A Kindberg, Raphael M Bendriem, Charles E Spivak, Melanie P Williams, Christopher T Richie, Annelie Handreck, Barbara S Mallon, Carl R Lupica, Da-Ting Lin, Brandon K Harvey, Deborah C Mash, William J Freed
Due to unavoidable confounding variables in the direct study of human subjects, it has been difficult to unravel the effects of prenatal cocaine exposure on the human fetal brain, as well as the cellular and biochemical mechanisms involved. Here, we propose a novel approach using a human pluripotent stem cell (hPSC)-based 3D neocortical organoid model. This model retains essential features of human neocortical development by encompassing a single self-organized neocortical structure, without including an animal-derived gelatinous matrix...
August 18, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Renata Szalai, Kinga Hadzsiev, Bela Melegh
The cytochrome P450 drug metabolizing enzymes are highly polymorphic and show inter-individual differences in variability in drug response, which varies widely also with ethnicity. This study aimed to summarize the available data on genetic polymorphisms associated with cytochrome enzymes conducted in Roma populations. Our goal was to compare the frequency of the variant alleles, genotypes and predicted phenotypes with corresponding rates from other populations. We carried out a systematic review including the papers published on the pharmacogenetically relevant variants of cytochrome P450 genes related to Roma population...
August 8, 2016: Current Medicinal Chemistry
S W Chan, Y Xiao, M Hu, O Q P Yin, T T W Chu, B S P Fok, V H L Lee, B Tomlinson
WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6β-hydroxycortisol (6β-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6β-OHF/F in healthy Chinese. METHODS: Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms...
October 2016: Journal of Clinical Pharmacy and Therapeutics
Yoichi Miyata, Nobuhisa Akamatsu, Yasuhiko Sugawara, Junichi Kaneko, Takehito Yamamoto, Hiroshi Suzuki, Junichi Arita, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Sumihito Tamura, Norihiro Kokudo
BACKGROUND The aim of the present study was to investigate the pharmacokinetics of the once-daily tacrolimus formulation (QD form) in relation to polymorphisms of the donor cytochrome P450 family 3 sub-family A polypeptide 5 (CYP3A5) gene and recipient adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1) gene. MATERIAL AND METHODS A total of 80 consecutive living-donor liver transplant (LDLT) recipients were started on the QD form of tacrolimus (day 1), and 60 patients were completely followed for 7 days early after liver transplantation in order to evaluate the pharmacokinetics...
2016: Annals of Transplantation: Quarterly of the Polish Transplantation Society
Thomas Vanhove, Hylke de Jonge, Henriëtte de Loor, Pieter Annaert, Ulf Diczfalusy, Dirk R J Kuypers
AIMS: We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients. METHODS: For a cohort of 147 patients, 8 hour area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4β-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe...
August 8, 2016: British Journal of Clinical Pharmacology
Shu Liu, Rong-Xin Chen, Jun Li, Yu Zhang, Xue-Ding Wang, Qian Fu, Ling-Yan Chen, Xiao-Man Liu, Hong-Bing Huang, Min Huang, Chang-Xi Wang, Jia-Li Li
AIM: Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients. METHODS: A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed...
September 2016: Acta Pharmacologica Sinica
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