Erythromycin-felodipine interaction: Magnitude, mechanism, and comparison with grapefruit juice

Objective: To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine, Methods: Felodipine, 10 mg extended release, was administered with 250 mi water, 250 mg erythromycin, or 250 mi grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day, Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied. Results: Compared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration-time profile (AUG), plasma peak drug concentrations (C-max), and apparent elimination half-life (t(1/2)); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, C-max, and t(1/2) but decreased dehydrofelodipine/felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced, These findings support inhibition of both metabolic pathways likely mediated by CPP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t(1/2). Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine C-max but not with relative felodipine t(1/2), suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination. Conclusions: Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism, Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall.