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The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers.
MedLine Citation:
PMID:  21673613     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVE: Telmisartan is mainly takenup into the liver by organic anion transporting polypeptide (OATP) 1B3, conjugated with glucuronate, and excreted into the bile. We investigated the relationship between genotypes of metabolizing enzymes and transporters and pharmacokinetics of telmisartan in clinical study. We also checked which enzymes are responsible for telmisartan glucuronidation. MATERIALS AND METHODS: We collected blood samples from 57 healthy volunteers who had participated in a clinical trial of telmisartan and examined the relationship between 14 mutations in six transporters/metabolic enzymes and pharmacokinetics of telmisartan. We also performed an in-vitro glucuronidation assay with recombinant uridine 5'-diphospho-glucuronosyltransferases isoforms and human liver microsomes. RESULTS: In the clinical study, area under the plasma concentration-time curve value from time zero to infinity, of telmisartan in heterozygotes of SLCO1B3 (encoding protein: OATP1B3) rs11045585 tended to be larger than that in homozygotes of wild-type alleles. Unexpectedly, 19 heterozygotes of UGT1A1*28, whose function was decreased, significantly increased its oral clearance compared with homozygotes of UGT1A1*1 alleles (1090±690 vs. 620±430 ml/min/body). Metabolic clearance of telmisartan in human liver microsomes obtained from individuals with UGT1A1*28/*28 was higher compared with that of UGT1A1*1/*1 (168±33 vs. 93.3±127.3 μl/min/mg protein). Although telmisartan was metabolized by multiple UGT isoforms, in-vitro experiments revealed that UGT1A3 was estimated to be predominantly involved in telmisartan glucuronidation in human hepatocytes. CONCLUSION: UGT1A1*28 was thought to enhance the protein expression of UGT1A3 as reported most recently (Riedmaier et al. Clin Pharmacol Ther 2010; 87:65-73) and thereby increase glucuronidation activity of telmisartan and decrease the plasma concentration of telmisartan.
Authors:
Akihiro Yamada; Kazuya Maeda; Naoki Ishiguro; Yasuhiro Tsuda; Takashi Igarashi; Thomas Ebner; Willy Roth; Shinichi Ikushiro; Yuichi Sugiyama
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-6-13
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  -     ISSN:  1744-6880     ISO Abbreviation:  -     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-6-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
aGraduate School of Pharmaceutical Sciences, The University of Tokyo bKobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Hyogo cDepartment of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan dBoehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
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