Comprehensive pharmacogenomic study reveals an important role of UGT1A3 in montelukast pharmacokinetics

Päivi Hirvensalo, Aleksi Tornio, Mikko Neuvonen, Tuija Tapaninen, Maria Paile-Hyvärinen, Vesa Kärjä, Ville T. Männistö, Jussi Pihlajamäki, Janne T. Backman, Mikko Niemi

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC(0-)) of montelukast (by 18% per copy of the minor allele; P=1.83 x 10(-10)). UGT1A3*2 was associated with increased AUC(0-) of montelukast acyl-glucuronide M1 and decreased AUC(0-) of hydroxymetabolites M5R, M5S, and M6 (P <10(-9)). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC(0-) of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC(0-) of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers.

Alkuperäiskielienglanti
LehtiClinical Pharmacology and Therapeutics
Vuosikerta104
Numero1
Sivut158-168
Sivumäärä11
ISSN0009-9236
DOI - pysyväislinkit
TilaJulkaistu - heinäkuuta 2018
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 317 Farmasia

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