In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases.

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Cardoso Jde O, Oliveira RV, Lu JB, Desta Z

In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases.

Drug Metab Dispos. 2015 Dec;43(12):1905-16. doi: 10.1124/dmd.115.065763.

PubMed ID

26374173 [ View in PubMed

]

Abstract

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 5'-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 ether-glucuronide. 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Montelukast	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Montelukast Lumacaftor	The serum concentration of Montelukast can be decreased when it is combined with Lumacaftor.