Premium
Gemfibrozil Markedly Increases the Plasma Concentrations of Montelukast: A Previously Unrecognized Role for CYP2C8 in the Metabolism of Montelukast
Author(s) -
Karonen T,
Filppula A,
Laitila J,
Niemi M,
Neuvonen P J,
Backman J T
Publication year - 2010
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.73
Subject(s) - montelukast , gemfibrozil , cmax , pharmacology , metabolite , chemistry , pharmacokinetics , crossover study , cyp2c8 , leukotriene e4 , leukotriene d4 , oral administration , active metabolite , medicine , endocrinology , leukotriene , placebo , metabolism , cyp3a4 , biochemistry , cytochrome p450 , cholesterol , alternative medicine , pathology , asthma
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 ( C max ), and elimination half‐life ( t 1/2 ) of montelukast 4.5‐fold, 1.5‐fold, and 3.0‐fold, respectively ( P < 0.001). After administration of gemfibrozil, the time to reach C max ( t max ) of the montelukast metabolite M6 was prolonged threefold ( P = 0.005), its AUC 0–7 was reduced by 40% ( P = 0.027), and the AUC 0–24 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 (IC 50 ) 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