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 ml water, 250 mg erythromycin, or 250 ml 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 (AUC), plasma peak drug concentration (Cmax), and apparent elimination half-life (t1/2); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, Cmax, and t1/2 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 CYP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t1/2. 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 Cmax but not with relative felodipine t1/2, 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.