UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics—A Comprehensive Pharmacogenomic Study
Päivi Hirvensalo, Aleksi Tornio, Terhi Launiainen, Maria Paile‐Hyvärinen, Tuija Tapaninen, Mikko Neuvonen, Janne T. Backman, Mikko Niemi
Abstract
To investigate how variability in multiple pharmacokinetic genes associates with telmisartan exposure, we determined telmisartan single‐dose (40 mg) pharmacokinetics and sequenced 379 genes in 188 healthy volunteers. Intronic UGT1A variants showed the strongest associations with the area under the plasma concentration‐time curve from zero hours to infinity (AUC 0–∞ ) and peak plasma concentration (C max ) of telmisartan. These variants were strongly linked with the increased function UGT1A3*2 allele, suggesting that it is the causative allele underlying these associations. In addition, telmisartan plasma concentrations were lower in men than in women. The UGT1A3*2 was associated with a 64% and 63% reduced AUC 0‐∞ of telmisartan in UGT1A3*2 heterozygous and homozygous men, respectively ( P = 1.21 × 10 −16 and 5.21 × 10 −8 ). In women, UGT1A3*2 heterozygosity and homozygosity were associated with 57% ( P = 1.54 × 10 −11 ) and 72% ( P = 3.31 × 10 −15 ) reduced AUC 0‐∞ , respectively. Furthermore, a candidate gene analysis suggested an association of UGT1A3*3 and the SLCO1B3 c.767G>C missense variant with telmisartan pharmacokinetics. A genotype score, which reflects the effects of sex and genetic variants on telmisartan AUC 0–∞ , associated with the effect of telmisartan on diastolic blood pressure. These data indicate that sex and UGT1A3 are major determinants and suggest a role for OATP1B3 in telmisartan pharmacokinetics.