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

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-infinity), 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-beta 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 micromol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.

Reevaluation of the Microsomal Metabolism of Montelukast: Major Contribution by CYP2C8 at Clinically Relevant Concentrations

“…In addition, our in vivo results are more consistent with the RAF approach (Karonen et al, 2010). In healthy volunteers, gemfibrozil, a strong in vivo CYP2C8 inhibitor (Backman et al, , 2009Niemi et al, 2003a,b;Tornio et al, 2008) increased the mean area under the plasma concentration-time curve of montelukast 4.5-fold, equivalent to an almost 80% reduction in oral clearance and reduced the area under the plasma concentration-time curve of M6 and M4 by 40 and Ͼ90%, respectively (Karonen et al, 2010). These findings are almost exactly in accordance with the RAF-based Ͼ70% contribution for CYP2C8, as well as with our in vitro data predicting a crucial role for CYP2C8 in M6 formation and its further metabolism to M4.…”

“…The RAF approach accounts for variations in both quantities and activities between HLM and recombinant P450 enzymes, and it has been shown to provide more reliable predictions than does the relative abundance method (Stringer et al, 2009). In addition, our in vivo results are more consistent with the RAF approach (Karonen et al, 2010). In healthy volunteers, gemfibrozil, a strong in vivo CYP2C8 inhibitor (Backman et al, , 2009Niemi et al, 2003a,b;Tornio et al, 2008) increased the mean area under the plasma concentration-time curve of montelukast 4.5-fold, equivalent to an almost 80% reduction in oral clearance and reduced the area under the plasma concentration-time curve of M6 and M4 by 40 and Ͼ90%, respectively (Karonen et al, 2010).…”

“…In agreement with previous studies , preliminary experiments indicated that M2 formation is catalyzed by CYP3A4 (and CYP3A5). However, the quantitative importance of M2 is negligible in humans Karonen et al, 2010;Singulair Clinical Pharmacology and Biopharmaceutics Review(s), http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/ 020829s000_Singular_Clin_Pharm_Biopharm.pdf). In addition, because of the montelukast sulfoxide impurity (ϳ1%) present in montelukast sodium, an accurate quantification of metabolite formation was not possible.…”

“…In our recently published in vivo study, the strong CYP2C8 inhibitor gemfibrozil raised the plasma exposure to montelukast in humans almost 5-fold, consistent with an important role for CYP2C8 in the metabolism of montelukast (Karonen et al, 2010). The present in vitro study was conducted to reevaluate the contributions of different P450 enzymes to the hepatic microsomal metabolism of montelukast at clinically relevant concentrations.…”

Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice

“…Host-and therapy-related determinants were explored for their potential association with ADRs. We focused on polymorphisms of two genes and alleles with a reported population prevalence of ⩾9%, namely CYP2C8*3, strongly associated with hepatic metabolism of montelukast [22,23], and SLCO2B1 that codes for the transporter OATP2B1 modulating intestinal and blood-brain barrier transport of montelukast [24,25]. Finally, in the nested matched-controlled cohort, we ascertained the relative incidence of neuropsychiatric ADRs leading to drug cessation in the montelukast versus ICS groups.…”