Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose.

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Ieiri I, Nishimura C, Maeda K, Sasaki T, Kimura M, Chiyoda T, Hirota T, Irie S, Shimizu H, Noguchi T, Yoshida K, Sugiyama Y

Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose.

Pharmacogenet Genomics. 2011 Aug;21(8):495-505. doi: 10.1097/FPC.0b013e3283489ce2.

PubMed ID

21691256 [ View in PubMed

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Abstract

OBJECTIVES: 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 mug), 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. CONCLUSION: 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Telmisartan	UDP-glucuronosyltransferase 1-3	Protein	Humans	Unknown	Substrate	Details