The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide

Objective: Our objective was to study the effects of the macrolide antibiot ic clarithromycin on the pharmacokinetics and pharmacodynamics of repaglini de, a novel short-acting antidiabetic drug. Methods: In a randomized, double-blind, 2-phase crossover study, 9 healthy volunteers were treated for 4 days with 250 mg oral clarithromycin or place bo twice daily. On day 5 they received a single dose of 250 mg clarithromyc in or placebo, and 1 hour later a single dose of 0.25 mg repaglinide was gi ven orally. Plasma repaglinide, serum insulin, and blood glucose concentrat ions were measured up to 7 hours. Results: Clarithromycin increased the mean total area under the concentrati on-time curve of repaglinide by 40% (P < .0001) and the peak plasma concent ration by 67% (P < .005) compared with placebo. The mean elimination half-l ife of repaglinide was prolonged from 1.4 to 1.7 hours (P < .05) by clarith romycin. Clarithromycin increased the mean incremental area under the conce ntration-time curve from 0 to 3 hours of serum insulin by 51% (P < .05) and the maximum increase in the serum insulin concentration by 61% (P < .01) c ompared with placebo. No statistically significant differences were found i n the blood glucose concentrations between the placebo and clarithromycin p hases. Conclusions: Even low doses of the cytochrome P4503A4 (CYP3A4) inhibitor cl arithromycin increase the plasma concentrations and effects of repaglinide. Concomitant use of clarithromycin or other potent inhibitors of CYP3A4 wit h repaglinide may enhance its blood glucose-lowering effect and increase th e risk of hypoglycemia.