¹Department of Medicine, London Health Sciences Centre, Ontario, Canada, Department of Physiology and Pharmacology, University of Western Ontario.

Correspondence: David G. Bailey, PhD, Department of Medicine, London Health Sciences Centre, Victoria Campus, 375 South St, London, Ontario, Canada N6A 4G5. E-mail: david.bailey@lhsc.on.ca

^*Supported by a grant from the Department of Medicine Research Development Fund, University of Western Ontario.

Presented in part at the 2002 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Atlanta, Georgia, March 23-27, 2002.

Received 1 October 2002; Accepted 1 February 2003.

Abstract

Objectives: Our objective was to assess the importance of bergamottin in drug interactions through comparisons between grapefruit juice and lime juice and the potential for drug interactions with red wine.

Methods: Bergamottin content and in vitro reversible/irreversible inhibition of cytochrome P450 (CYP) 3A4 monooxygenase activities were determined for grapefruit and lime juices. The oral pharmacokinetics of felodipine and its primary metabolite (dehydrofelodipine) were determined with 250 mL of grapefruit juice, one quarter–strength lime juice, red wine, or water in a randomized crossover study.

Results: Bergamottin concentrations in grapefruit and lime juices were 25 and 100 mol/L, respectively. For reversible inhibition, log volume-residual CYP3A4 activity relationships for grapefruit and lime juices had negative linear slopes that were parallel. The curve for grapefruit juice was 4.0-fold right-shifted, as compared with that for lime juice. For irreversible inhibition, the curves for grapefruit and lime juices were 4.0- and 1.4-fold left-shifted, as compared with those for reversible inhibition, respectively. Grapefruit juice increased the mean felodipine area under the plasma concentration-time curve (AUC) (mean SE, 55 9 nmol h/L versus 29 6 nmol h/L; P < .05) and the plasma peak drug concentration (16 3 nmol/L versus 8 2 nmol/L, P < .05) and decreased the dehydrofelodipine/felodipine AUC ratio compared with those of water. One quarter–strength lime juice did not alter mean values. However, the changes in individual felodipine AUC after grapefruit juice and lime juice correlated (r² = 0.95) with a low slope (0.36). One quarter–strength lime juice more than doubled felodipine AUC and plasma peak drug concentration in 2 subjects. Red wine prolonged mean felodipine time to plasma peak drug concentration. Felodipine concentrations were low and peaked abruptly in 4 subjects. Adverse effects occurred in 1 subject.

Conclusions: Bergamottin and reversible inhibition are not the primary substance and mechanism responsible for inhibition of CYP3A4 activity clinically. Red wine can cause dose dumping of extended-release felodipine in certain individuals.