A1 Refereed original research article in a scientific journal
Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics
Authors: Hirvensalo P, Tornio A, Neuvonen M, Tapaninen T, Paile-Hyvarinen M, Karja V, Mannisto VT, Pihlajamaki J, Backman JT, Niemi M
Publisher: WILEY
Publication year: 2018
Journal: Clinical Pharmacology and Therapeutics
Journal name in source: CLINICAL PHARMACOLOGY & THERAPEUTICS
Journal acronym: CLIN PHARMACOL THER
Volume: 104
Issue: 1
First page : 158
Last page: 168
Number of pages: 11
ISSN: 0009-9236
DOI: https://doi.org/10.1002/cpt.891
Abstract
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.
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.
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