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Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations.
Drug Metab Dispos. 2011 May; 39(5):904-11.DM

Abstract

According to published in vitro studies, cytochrome P450 3A4 catalyzes montelukast 21-hydroxylation (M5 formation), whereas CYP2C9 catalyzes 36-hydroxylation (M6), the primary step in the main metabolic pathway of montelukast. However, montelukast is a selective competitive CYP2C8 inhibitor, and our recent in vivo studies suggest that CYP2C8 is involved in its metabolism. We therefore reevaluated the contributions of different cytochrome P450 (P450) enzymes, particularly that of CYP2C8, to the hepatic microsomal metabolism of montelukast using clinically relevant substrate concentrations in vitro. The effects of P450 isoform inhibitors on montelukast metabolism were examined using pooled human liver microsomes, and montelukast oxidations by human recombinant CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 were investigated. The results verified the central role of CYP3A4 in M5 formation. The CYP2C8 inhibitors gemfibrozil 1-O-β glucuronide and trimethoprim inhibited the depletion of 0.02 μM montelukast and formation of M6 from 0.05 μM montelukast more potently than did the CYP2C9 inhibitor sulfaphenazole. Likewise, recombinant CYP2C8 catalyzed montelukast depletion and M6 formation at a 6 times higher intrinsic clearance than did CYP2C9, whereas other P450 isoforms produced no M6. On the basis of depletion of 0.02 μM montelukast, CYP2C8 was estimated to account for 72% of the oxidative metabolism of montelukast in vivo, with a 16% contribution for CYP3A4 and 12% for CYP2C9. Moreover, CYP2C8 catalyzed the further metabolism of M6 more actively than did any other P450. In conclusion, CYP2C8 plays a major role in the main metabolic pathway of montelukast at clinically relevant montelukast concentrations in vitro.

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Publisher Full Text

Authors+Show Affiliations

Filppula AM
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Laitila J
No affiliation info available
Neuvonen PJ
No affiliation info available
Backman JT
No affiliation info available

MeSH

AcetatesAryl Hydrocarbon HydroxylasesCytochrome P-450 CYP2C8Cytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemHumansHydroxylationIsoenzymesLeukotriene AntagonistsLeukotrienesMicrosomes, LiverModels, TheoreticalOxidation-ReductionQuinolinesRecombinant ProteinsTime Factors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21289076

Clinical Trial Links

Functional Dyspepsia (FD) - Clinical Response to Montelukast in Children

Citation

Filppula, Anne M., et al. "Reevaluation of the Microsomal Metabolism of Montelukast: Major Contribution By CYP2C8 at Clinically Relevant Concentrations." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 39, no. 5, 2011, pp. 904-11.
Filppula AM, Laitila J, Neuvonen PJ, et al. Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations. Drug Metab Dispos. 2011;39(5):904-11.
Filppula, A. M., Laitila, J., Neuvonen, P. J., & Backman, J. T. (2011). Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 39(5), 904-11. https://doi.org/10.1124/dmd.110.037689
Filppula AM, et al. Reevaluation of the Microsomal Metabolism of Montelukast: Major Contribution By CYP2C8 at Clinically Relevant Concentrations. Drug Metab Dispos. 2011;39(5):904-11. PubMed PMID: 21289076.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations. AU - Filppula,Anne M, AU - Laitila,Jouko, AU - Neuvonen,Pertti J, AU - Backman,Janne T, Y1 - 2011/02/02/ PY - 2011/2/4/entrez PY - 2011/2/4/pubmed PY - 2011/12/31/medline SP - 904 EP - 11 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 39 IS - 5 N2 - According to published in vitro studies, cytochrome P450 3A4 catalyzes montelukast 21-hydroxylation (M5 formation), whereas CYP2C9 catalyzes 36-hydroxylation (M6), the primary step in the main metabolic pathway of montelukast. However, montelukast is a selective competitive CYP2C8 inhibitor, and our recent in vivo studies suggest that CYP2C8 is involved in its metabolism. We therefore reevaluated the contributions of different cytochrome P450 (P450) enzymes, particularly that of CYP2C8, to the hepatic microsomal metabolism of montelukast using clinically relevant substrate concentrations in vitro. The effects of P450 isoform inhibitors on montelukast metabolism were examined using pooled human liver microsomes, and montelukast oxidations by human recombinant CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 were investigated. The results verified the central role of CYP3A4 in M5 formation. The CYP2C8 inhibitors gemfibrozil 1-O-β glucuronide and trimethoprim inhibited the depletion of 0.02 μM montelukast and formation of M6 from 0.05 μM montelukast more potently than did the CYP2C9 inhibitor sulfaphenazole. Likewise, recombinant CYP2C8 catalyzed montelukast depletion and M6 formation at a 6 times higher intrinsic clearance than did CYP2C9, whereas other P450 isoforms produced no M6. On the basis of depletion of 0.02 μM montelukast, CYP2C8 was estimated to account for 72% of the oxidative metabolism of montelukast in vivo, with a 16% contribution for CYP3A4 and 12% for CYP2C9. Moreover, CYP2C8 catalyzed the further metabolism of M6 more actively than did any other P450. In conclusion, CYP2C8 plays a major role in the main metabolic pathway of montelukast at clinically relevant montelukast concentrations in vitro. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/21289076/Reevaluation_of_the_microsomal_metabolism_of_montelukast:_major_contribution_by_CYP2C8_at_clinically_relevant_concentrations_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21289076 DB - PRIME DP - Unbound Medicine ER -