Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics.

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 × 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. [ABSTRACT FROM AUTHOR]