title: The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers.
abstract: OBJECTIVE
  Telmisartan is mainly taken up 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.
  
  
  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±27.3 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.
  
  
  CONCLUSIONS
  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.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebner
authors.forename: Willy
authors.initials: W
authors.lastname: Roth
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ikushiro
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D001565:Benzoates / Q000097:blood / Q000493:pharmacokinetics*; D001646:Bile / Q000201:enzymology; D054316:Biomarkers, Pharmacological; D002986:Clinical Trials as Topic; D056726:Genetic Association Studies; D005838:Genotype; D005965:Glucuronates / Q000097:blood; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D027361:Organic Anion Transporters / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077333:Telmisartan; D055815:Young Adult
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D054316:Biomarkers, Pharmacological; D005965:Glucuronates; D027361:Organic Anion Transporters; C122075:UDP-glucuronosyltransferase, UGT1A3; D014453:Glucuronosyltransferase; D000077333:Telmisartan