title: Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose.
abstract: OBJECTIVE
  In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms.
  
  
  METHODS
  Telmisartan was orally administered at MD condition (100 μg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed.
  
  
  RESULTS
  No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD.
  
  
  CONCLUSIONS
  The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Chisa
authors.initials: C
authors.lastname: Nishimura
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sasaki
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyoda
authors.forename: Tekeshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Shin
authors.initials: S
authors.lastname: Irie
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Takanori
authors.initials: T
authors.lastname: Noguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001565:Benzoates / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077333:Telmisartan; D000099148:UGT1A1 Enzyme
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D014453:Glucuronosyltransferase; D029362:Organic Anion Transporters, Sodium-Independent; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077333:Telmisartan; D000099148:UGT1A1 Enzyme; C421209:SLCO1B3 protein, human