In Vitro Metabolism of Montelukast by Cytochrome P450S and UDP-Glucuronosyltransferases

被引:32
作者
Cardoso, Josiane de Oliveira [1 ,2 ]
Oliveira, Regina Vincenzi [2 ]
Lu, Jessica Bo Li [1 ]
Desta, Zeruesenay [1 ]
机构
[1] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA
[2] Univ Fed Sao Carlos, Dept Chem, BR-13560 Sao Carlos, SP, Brazil
基金
美国国家卫生研究院;
关键词
RECEPTOR ANTAGONIST; PLASMA-CONCENTRATIONS; DRUG-INTERACTION; GEMFIBROZIL; POTENT; PHARMACOKINETICS; CYP2C8; INHIBITION; GLUCURONIDATION; LEUKOTRIENES;
D O I
10.1124/dmd.115.065763
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Montelukast has been recommended as a selective in vitro and in vivo probe of cytochrome P450 (P450) CYP2C8 activity, but its selectivity toward this enzyme remains unclear. We performed detailed characterization of montelukast metabolism in vitro using human liver microsomes (HLMs), expressed P450s, and uridine 59-diphospho-glucuronosyltransferases (UGTs). Kinetic and inhibition experiments performed at therapeutically relevant concentrations reveal that CYP2C8 and CYP2C9 are the principal enzymes responsible for montelukast 36-hydroxylation to 1,2-diol. CYP3A4 was the main catalyst of montelukast sulfoxidation and stereoselective 21-hydroxylation, and multiple P450s participated in montelukast 25-hydroxylation. We confirmed direct glucuronidation of montelukast to an acyl-glucuronide. We also identified a novel peak that appears consistent with an etherglucuronide. Kinetic analysis in HLMs and experiments in expressed UGTs indicate that both metabolites were exclusively formed by UGT1A3. Comparison of in vitro intrinsic clearance in HLMs suggest that direct glucuronidation may play a greater role in the overall metabolism of montelukast than does P450-mediated oxidation, but the in vivo contribution of UGT1A3 needs further testing. In conclusion, our in vitro findings provide new insight toward montelukast metabolism. The utility of montelukast as a probe of CYP2C8 activity may be compromised owing to involvement of multiple P450s and UGT1A3 in its metabolism.
引用
收藏
页码:1905 / 1916
页数:12
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