Articles

Gemfibrozil Markedly Increases the Plasma Concentrations of Montelukast: A Previously Unrecognized Role for CYP2C8 in the Metabolism of Montelukast

T Karonen

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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A Filppula

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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J Laitila

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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M Niemi

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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P J Neuvonen

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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J T Backman

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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First published: 30 June 2010
Cited by: 11

Abstract

According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration–time curve (AUC)0–∞, peak plasma concentration (Cmax), and elimination half‐life (t1/2) of montelukast 4.5‐fold, 1.5‐fold, and 3.0‐fold, respectively (P < 0.001). After administration of gemfibrozil, the time to reach Cmax (tmax) of the montelukast metabolite M6 was prolonged threefold (P = 0.005), its AUC0–7 was reduced by 40% (P = 0.027), and the AUC0–24 of the secondary metabolite M4 was reduced by >90% (P < 0.001). In human liver microsomes, gemfibrozil 1‐O‐β glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35‐fold more potently than did gemfibrozil (half‐maximal inhibitory concentration (IC50) 3.0 and 107 µmol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.

Clinical Pharmacology & Therapeutics (2010) 88 2, 223–230. doi: 10.1038/clpt.2010.73

Number of times cited according to CrossRef: 11

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