Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
Clin Pharmacol Ther. 2018 Jul;104(1):158-168. doi: 10.1002/cpt.891. Epub 2017 Nov 6.
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 UGT1A32, associated with reduced area under the plasma concentration-time curve (AUC ) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10 ). UGT1A32 was associated with increased AUC of montelukast acyl-glucuronide M1 and decreased AUC of hydroxymetabolites M5R, M5S, and M6 (P < 10 ). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC 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.
为了确定孟鲁司特暴露个体间变异性的遗传基础，我们测定了 191 名健康志愿者的药代动力学，并对 379 个药代动力学基因进行了测序。一个内含子单核苷酸变异（SNV）与 UGT1A32 强烈连锁，与孟鲁司特的血浆浓度-时间曲线下面积（AUC）降低有关（每个次要等位基因的副本减少 18%；P=1.83×10）。UGT1A32 与孟鲁司特酰葡萄糖醛酸苷 M1 的 AUC 增加和羟基代谢物 M5R、M5S 和 M6 的 AUC 降低有关（P<10）。此外，SLCO1B1 和 ABCC9 的 SNV 与 M1 和 M5R 的 AUC 分别相关。此外，候选基因分析表明，CYP2C8 和 ABCC9 的 SNV 也影响孟鲁司特的 AUC。发现的 UGT1A3 和 ABCC9 变体与人类肝样本中相应基因的表达增加有关。孟鲁司特及其羟基代谢物在体外由 UGT1A3 进行葡萄糖醛酸化。这些结果表明 UGT1A3 在孟鲁司特的药代动力学中起着重要作用，特别是在 UGT1A3*2 携带者中。
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