Effect of clarithromycin and fluconazole on the pharmacokinetics of montelukast in human volunteers

Abstract

Clarithromycin increased the plasma concentrations of montelukast whereas fluconazole reduced the plasma concentrations of montelukast. The mechanism of the interaction is probably due to interference of the interacting drugs with transporters mediating the uptake of montelukast.

In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases

“…It is improbable that this effect is mediated via CYP3A or CYP2C8, because itraconazole, another strong CYP3A4 inhibitor, had no effect on the systemic exposure of montelukast (Karonen et al, 2012), and clarithromycin and fluconazole are not known to inhibit CYP2C8. These data suggest involvement of yet unidentified pathways of montelukast disposition, possibly drug transporters (Hegazy et al, 2012). In summary, we present new insight into montelukast metabolism in vitro (Fig.…”

“…While gemfibrozil potently inhibits CYP2C9 in vitro (Wen et al, 2001), the (Niemi et al, 2001). The mechanism-based inactivator of CYP3A4 clarithromycin increases montelukast exposure by ;144%, whereas fluconazole decreased montelukast exposure by .30% (Hegazy et al, 2012). It is improbable that this effect is mediated via CYP3A or CYP2C8, because itraconazole, another strong CYP3A4 inhibitor, had no effect on the systemic exposure of montelukast (Karonen et al, 2012), and clarithromycin and fluconazole are not known to inhibit CYP2C8.…”

“…The potential for the presence of alternative mechanisms in montelukast disposition is supported by patterns of drug-drug interactions with montelukast. For example, the mechanism-based inactivator of CYP3A4, clarithromycin, increased montelukast AUC 0-' by approximately 144% (Hegazy et al, 2012), whereas itraconazole (a potent CYP3A inhibitor) did not affect its disposition (Karonen et al, 2012). Clarithromycin is not known to inhibit CYP2C8.…”

Amenamevir: Studies of Potential CYP2C8‐ and CYP2B6‐Mediated Pharmacokinetic Interactions With Montelukast and Bupropion in Healthy Volunteers

“…A sample size of 24 subjects for the montelukast study was selected based on a statistical power calculation. From published studies, estimates of between‐subject percentage coefficient of variation (%CV) for C max and AUC 0‐∞ were 20% to 30% . Statistical power was estimated by 10,000 simulations using the model below.…”

“…It is metabolized to its primary metabolite methyl‐hydroxymontelukast (M6) via 36‐hydroxylation by CYP2C8, which is also responsible for subsequent conversion to the secondary metabolite montelukast dicarboxylic acid (M4). CYP2C8 is thought to account for 70% to 80% of montelukast's metabolism in vivo, with most of the remainder accounted for by CYP3A4‐mediated conversion to M5a and M5b metabolites: less than 0.2% is eliminated in urine . This, together with its benign safety profile, makes it an appropriate choice as a CYP2C8 probe in healthy subjects. Bupropion is an orally available antidepressant and nonnicotine smoking cessation aid that is thought to exert its activity by reuptake inhibition of norepinephrine and dopamine and by noncompetitive antagonism of nicotinic acetylcholine receptors .…”