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UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics-A Comprehensive Pharmacogenomic Study
Tekijät: Hirvensalo P, Tornio A, Launiainen T, Paile-Hyvarinen M, Tapaninen T, Neuvonen M, Backman JT, Niemi M
Kustantaja: WILEY
Julkaisuvuosi: 2020
Journal: Clinical Pharmacology and Therapeutics
Tietokannassa oleva lehden nimi: CLINICAL PHARMACOLOGY & THERAPEUTICS
Lehden akronyymi: CLIN PHARMACOL THER
Vuosikerta: 108
Numero: 4
Aloitussivu: 885
Lopetussivu: 895
Sivujen määrä: 11
ISSN: 0009-9236
DOI: https://doi.org/10.1002/cpt.1928
Tiivistelmä
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. IntronicUGT1Avariants showed the strongest associations with the area under the plasma concentration-time curve from zero hours to infinity (AUC(0-infinity)) and peak plasma concentration (C-max) of telmisartan. These variants were strongly linked with the increased functionUGT1A3*2allele, suggesting that it is the causative allele underlying these associations. In addition, telmisartan plasma concentrations were lower in men than in women. TheUGT1A3*2was associated with a 64% and 63% reduced AUC(0-infinity)of telmisartan inUGT1A3*2heterozygous and homozygous men, respectively (P = 1.21 x 10(-16)and 5.21 x 10(-8)). In women,UGT1A3*2heterozygosity and homozygosity were associated with 57% (P = 1.54 x 10(-11)) and 72% (P = 3.31 x 10(-15)) reduced AUC(0-infinity), respectively. Furthermore, a candidate gene analysis suggested an association ofUGT1A3*3and theSLCO1B3c.767G>C missense variant with telmisartan pharmacokinetics. A genotype score, which reflects the effects of sex and genetic variants on telmisartan AUC(0-infinity), 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.
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. IntronicUGT1Avariants showed the strongest associations with the area under the plasma concentration-time curve from zero hours to infinity (AUC(0-infinity)) and peak plasma concentration (C-max) of telmisartan. These variants were strongly linked with the increased functionUGT1A3*2allele, suggesting that it is the causative allele underlying these associations. In addition, telmisartan plasma concentrations were lower in men than in women. TheUGT1A3*2was associated with a 64% and 63% reduced AUC(0-infinity)of telmisartan inUGT1A3*2heterozygous and homozygous men, respectively (P = 1.21 x 10(-16)and 5.21 x 10(-8)). In women,UGT1A3*2heterozygosity and homozygosity were associated with 57% (P = 1.54 x 10(-11)) and 72% (P = 3.31 x 10(-15)) reduced AUC(0-infinity), respectively. Furthermore, a candidate gene analysis suggested an association ofUGT1A3*3and theSLCO1B3c.767G>C missense variant with telmisartan pharmacokinetics. A genotype score, which reflects the effects of sex and genetic variants on telmisartan AUC(0-infinity), 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.
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