Bergamottin contribution to the grapefruit juice-felodipine interaction and disposition in humans

• Published in: Clinical pharmacology and therapeutics 2004-12, Vol.76 (6), p.607-617
• Main Authors: Goosen, Theunis C., Cillié, Doré, Bailey, David G., Yu, Chongwoo, He, Kan, Hollenberg, Paul F., Woster, Patrick M., Cohen, Lucinda, Williams, J. Andrew, Rheeders, Malie, Dijkstra, H. Paul
• Format: Article
• Language: English
• Subjects: Adult; Area Under Curve; Biological and medical sciences; Biological Availability; Biotransformation; Calcium Channel Blockers - pharmacokinetics; Calcium Channel Blockers - pharmacology; Capsules; Chromatography, High Pressure Liquid; Citrus - chemistry; Cross-Over Studies; Delayed-Action Preparations; Felodipine - pharmacokinetics; Felodipine - pharmacology; Female; Food-Drug Interactions; Furocoumarins - administration & dosage; Furocoumarins - pharmacology; Humans; Male; Medical sciences; Pharmacology. Drug treatments; Spectrophotometry, Ultraviolet
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2004.08.019

Objectives Our objectives were to evaluate the contribution of bergamottin to the grapefruit juice–felodipine interaction and to characterize bergamottin disposition. Methods In this study 250 mL grapefruit juice; 2‐, 6‐, or 12‐mg capsules of bergamottin plus water; or water was administered with 5 mg extended‐release felodipine to 11 volunteers in a partially randomized, 5‐way crossover study. Plasma concentrations of felodipine, its primary metabolite (dehydrofelodipine), bergamottin, and 6′,7′‐dihydroxybergamottin were determined. Results Grapefruit juice (containing 1.7 mg bergamottin) increased peak plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) of felodipine by 89% (P < .025) and 54% (P < .025), respectively, compared with water. With 2 mg bergamottin, felodipine Cmax increased by 33% (P < .05). The increase by bergamottin was markedly variable among individuals (range, −33% to 125%). With 6 mg bergamottin, felodipine Cmax was enhanced by 35% (P < .025), and with 12 mg bergamottin, felodipine Cmax increased by 40% (P < .05) and AUC increased by 37% (P < .05) compared with water. Bergamottin measured in plasma after administration of 6 and 12 mg produced Cmax values of 2.1 and 5.9 ng/mL, respectively, and times to reach Cmax of 0.8 and 1.1 hours, respectively. The bergamottin metabolite 6′,7′‐dihydroxybergamottin was detected in plasma of some subjects after bergamottin administration. Conclusions Bergamottin enhanced the oral bioavailability of felodipine and may cause a clinically relevant drug interaction in susceptible individuals. Grapefruit juice–drug interactions likely also involve other furanocoumarins, possibly acting in combination by additive or synergistic mechanisms. Bergamottin has systemic availability and is metabolized in vivo to 6′,7′‐dihydroxybergamottin. Clinical Pharmacology & Therapeutics (2004) 76, 607–617; doi: 10.1016/j.clpt.2004.08.019