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 felodip ine, Methods: Felodipine, 10 mg extended release, was administered wit h 250 mi water, 250 mg erythromycin, or 250 mi grapefruit juice in a r andomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that st udy day, Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite we re studied. Results: Compared with water, erythromycin produced severa lfold higher felodipine area under the plasma drug concentration-time profile (AUG), plasma peak drug concentrations (C-max), and apparent e limination 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 t he M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were r educed, These findings support inhibition of both metabolic pathways l ikely mediated by CPP3A4. Grapefruit juice produced similar mean effec ts but did not prolong felodipine or dehydrofelodipine t(1/2). Individ ually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin com pared with grapefruit juice) correlated with relative felodipine C-max but not with relative felodipine t(1/2), suggesting felodipine AUC di ffered between these treatments, mainly from factors affecting presyst emic drug elimination. Conclusions: Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug met abolism, Although erythromycin and grapefruit juice shared a common me chanism, erythromycin likely reduced felodipine biotransformation at t he gut wall and liver, whereas single-dose grapefruit juice had an eff ect mainly at the gut wall.