Gemfibrozil markedly increases the plasma concentrations of montelukast: A previously unrecognized role for CYP2c8 in the metabolism of montelukast

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 10mg 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 (IC₅₀) 3.0 and 107μmol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.