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

Clinical pharmacology and therapeutics 2020 Oct

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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 (AUC0-∞ ) and peak plasma concentration (Cmax ) 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 AUC0-∞ 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 AUC0-∞ , 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 AUC0-∞ , 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. © 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Citation

Päivi Hirvensalo, Aleksi Tornio, Terhi Launiainen, Maria Paile-Hyvärinen, Tuija Tapaninen, Mikko Neuvonen, Janne T Backman, Mikko Niemi. UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics-A Comprehensive Pharmacogenomic Study. Clinical pharmacology and therapeutics. 2020 Oct;108(4):885-895