Effects of clarithromycin and grapefruit juice on the pharmacokinetics of glibenclamide

Aims Case reports suggest that clarithromycin can increase the glucose-lowering effect of glibenclamide which is metabolized mainly by CYP2C9 and is a substrate for P-glycoprotein and OATP2B1. Our objective was to evaluate whether the P-glycoprotein inhibitor, clarithromycin, increases and the putative OATP2B1 inhibitor, grapefruit juice, decreases plasma concentrations of glibenclamide. Methods In a randomized three-phase crossover study, 12 subjects ingested 250 mg clarithromycin or placebo twice daily or 200 ml grapefruit juice three times daily for 2 days. On day 3, they ingested 0.875 mg glibenclamide with sugar water or grapefruit juice. Concentrations of glibenclamide and clarithromycin in plasma, glucose in blood, and excretion of hydroxyglibenclamide into urine were measured up to 12 h. Results Clarithromycin increased the peak concentration (C-max ) of glibenclamide to 1.25-fold (95% confidence interval (CI) 1.12, 1.40; P < 0.01) and the area under the plasma concentration-time curve to 1.35-fold (95% CI 1.21, 1.50; P < 0.01) compared with the placebo phase. The time to C-max , the half-life of glibenclamide, and the amount of hydroxyglibenclamide excreted into urine remained unaltered. Grapefruit juice did not change the pharmacokinetics of glibenclamide. Clarithromycin concentrations implied a good compliance. Blood glucose did not deviate between the phases. Conclusions Clarithromycin increased plasma concentrations of glibenclamide, possibly by inhibiting P-glycoprotein in the intestinal wall. Although not seen with the present study design, clarithromycin may enhance the effect of glibenclamide by increasing plasma glibenclamide concentrations, which warrants close monitoring of blood glucose during their co-administration. Grapefruit juice had no effect on glibenclamide pharmacokinetics.