Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide

Abstract

Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide Background and Objective: The antidiabetic repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4. Telithromycin, an antimicrobial agent, inhibits CYP3A4 in vitro and in vivo. Montelukast, an antiasthmatic drug, is a potent inhibitor of CYP2C8 in vitro. We studied the effects of telithromycin, montelukast, and the combination of telithromycin and montelukast on the pharmacokinetics and pharmacodynamics of repaglinide. Methods: In a randomized 4-phase crossover study, 12 healthy volunteers received 800 mg telithromycin, 10 mg montelukast, both telithromycin and montelukast, or placebo once daily for 3 days. On day 3, they ingested a single 0.25-mg dose of repaglinide. Plasma and urine concentrations of repaglinide and its metabolites M1, M2, and M4, as well as blood glucose concentrations, were measured for 12 hours. Results: Telithromycin alone raised the mean peak plasma repaglinide concentration to 138% (range, 91%-209%; P ‫؍‬ .006) and the total area under the plasma concentration-time curve from 0 hours to infinity [AUC(0-ؕ)] of repaglinide to 177% (range, 125%-257%; P < .001) of control (placebo). Telithromycin reduced the AUC(0-ؕ) ratio of the metabolite M1 to repaglinide by 68% (P < .001) and the urinary excretion ratio of M1 to repaglinide by 77% (P ‫؍‬ .001). In contrast to previous estimates based on in vitro CYP2C8 inhibition data, montelukast had no significant effect on the pharmacokinetics of repaglinide or its metabolites and did not significantly alter the effect of telithromycin on repaglinide pharmacokinetics. Telithromycin, unlike montelukast, lowered the maximum blood glucose concentration (P ‫؍‬ .002) and mean blood glucose concentration from 0 to 3 hours (P ‫؍‬ .008) after repaglinide intake, as compared with placebo. Conclusions: Telithromycin increases the plasma concentrations and blood glucose-lowering effect of repaglinide by inhibiting its CYP3A4-catalyzed biotransformation and may increase the risk of hypoglycemia. Unexpectedly, montelukast has no significant effect on repaglinide pharmacokinetics, suggesting that it does not significantly inhibit CYP2C8 in vivo. The low free fraction of montelukast in plasma may explain the lack of effect on CYP2C8 in vivo, despite the low in vitro inhibition constant, highlighting the importance of incorporating plasma protein binding to interaction predictions. (Clin Pharmacol Ther 2006;79:231-42.)

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

“…Although montelukast has been identified as a highly potent and selective competitive inhibitor of CYP2C8 in vitro (Walsky et al, 2005a,b), it does not inhibit CYP2C8 in vivo (Jaakkola et al, 2006;Kajosaari et al, 2006;Kim et al, 2007). The lack of an in vivo inhibitory effect suggests that the concentrations of montelukast in hepatocytes are much lower than its K i for CYP2C8 (Ͻ0.15 M), consistent with the small unbound fraction of montelukast in plasma.…”

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…In another study, the inhibition of CYP2C8 by montelukast was found to be competitive and selective, with reversible inhibition constants (K i ) ranging from 0.0092 to 0.15 mM, depending on the protein concentration used in the incubation (Walsky et al, 2005b). However, despite their strong inhibitory effect on CYP2C8 in vitro, neither montelukast nor zafirlukast affected the pharmacokinetics of CYP2C8 substrate drugs in vivo (Jaakkola et al, 2006b;Kajosaari et al, 2006b;Kim et al, 2007). The lack of in vivo effect is likely explained by their extensive plasma protein binding (.99%) (FDA, 1998;Dekhuijzen and Koopmans, 2002).…”

A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance

“…The same study resulted in no fold change in the M2/M4 AUC ratio when the dosing interval was Ͼ24 h, reflecting the CYP2C8 half-life. The CYP3A4 inhibitor telithromycin led to a 4-fold increase in the M2/M1 AUC ratio in comparison with the control (Kajosaari et al, 2006b). …”