UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics-A Comprehensive Pharmacogenomic Study

Show full item record



Permalink

http://hdl.handle.net/10138/320767

Citation

Hirvensalo , P , Tornio , A , Launiainen , T , Paile-Hyvärinen , M , Tapaninen , T , Neuvonen , M , Backman , J T & Niemi , M 2020 , ' UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics-A Comprehensive Pharmacogenomic Study ' , Clinical Pharmacology and Therapeutics , vol. 108 , no. 4 , pp. 885-895 . https://doi.org/10.1002/cpt.1928

Title: UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics-A Comprehensive Pharmacogenomic Study
Author: Hirvensalo, Päivi; Tornio, Aleksi; Launiainen, Terhi; Paile-Hyvärinen, Maria; Tapaninen, Tuija; Neuvonen, Mikko; Backman, Janne T.; Niemi, Mikko
Other contributor: University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB










Date: 2020-10
Language: eng
Number of pages: 11
Belongs to series: Clinical Pharmacology and Therapeutics
ISSN: 0009-9236
DOI: https://doi.org/10.1002/cpt.1928
URI: http://hdl.handle.net/10138/320767
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. 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.
Subject: URIDINE DIPHOSPHO-GLUCURONOSYLTRANSFERASES
II RECEPTOR ANTAGONIST
HAPLOTYPE RECONSTRUCTION
ORAL MICRODOSE
HEALTHY
POLYMORPHISMS
SAFETY
GLUCURONIDATION
TRANSPORTERS
PROFILES
3111 Biomedicine
317 Pharmacy
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
cpt.1928_1.pdf 487.9Kb PDF View/Open
UGT1A3_and_sex_ ... _pharmacogenomic_study.pdf 15.02Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record