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

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 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. 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.

Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus.

Recent advances in genome research have enabled the identification of new genomic variations that are associated with type 2 diabetes mellitus (T2DM). Via fine mapping of SNPs in a candidate region of chromosome 21q, the current study identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the beta cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals in three independent Japanese sample sets (p = 2.5 x 10(-7), odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76-3.67) and with unstratified T2DM (p = 6.7 x 10(-6), OR = 1.76, 95% CI = 1.37-2.25). The diabetes risk allele frequency was, however, very low among Europeans in whom no association between this variant and T2DM could be shown. Functional analysis in human embryonic kidney 293 cells demonstrated that the risk allele of the synonymous SNP in exon 4 increased KCNJ15 expression via increased mRNA stability, which resulted in the higher expression of protein as compared to that of the nonrisk allele. We also showed that KCNJ15 is expressed in human pancreatic beta cells. In conclusion, we demonstrated a significant association between a synonymous variant in KCNJ15 and T2DM in lean Japanese patients with T2DM, suggesting that KCNJ15 is a previously unreported susceptibility gene for T2DM among Asians.