Grapefruit juice-felodipine interaction: reproducibility and characterization with the extended release drug formulation
1. Felodipine 10 mg extended release was administered with 250 ml regular-strength grapefruit juice or water in a randomized crossover manner followed by a second grapefruit juice treatment in 12 healthy men. The pharmacokinetics of felodipine and primary oxidative metabolite, dehydrofelodipine, were evaluated.
2. Initial grapefruit juice treatment increased felodipine AUC (mean ± s.d.; 56.6 ± 21.9 vs 28.1 ± 11.5 ng ml-1 h; P < 0.001) and Cmax, (8.1 ± 2.5 vs 3.3 ± 1.2 ng ml-'; P < 0.001) compared with water. Felodipine tmax (median; 2.8 vs 3.0 h) and t1/2 (7.3 ± 3.7 vs 6.9 ± 3.6 h) were not altered.
3. Readministration of felodipine with grapefruit juice produced mean felodipine AUC (61.5 ± 32.2 ng ml-' h) and Cmax (8.4 ± 4.8 ng ml-') which were similar to the initial grapefruit juice treatment 1-3 weeks previously. Felodipine AUC (r = 0.73, P < 0.01) and Cmax(r = 0.69, P < 0.02) correlated between grapefruit juice treatments among individuals.
4. The % increase in felodipine AUC with the initial grapefruit juice treatment compared with water correlated with the % increase in felodipine C.a@ among individuals (r = 0.80, P < 0.01). Dehydrofelodipine AUC (74.7 ± 28.7 vs 48.5 ± 16.3 ng ml- h; P< 0.01) and Cmax (12.' ± 2.9 vs 7.9 ± 2.6 ng ml-h; P< 0.01) were augmented with grapefruit juice compared with water. The ratios of dehydrofelodipine/felodipine for AUC (1.35 ± 0.26 vs 1.78 ± 0.23; P < 0.001) and at felodipine Cmax (1.55 ± 0.35 vs 2.33 ± 0.29; P < 0.001) were reduced.
5. There was a negative correlation between felodipine AUC with water and the % increase in AUC among individuals with data combined from both grapefruit juice treatments (r = -0.47; P < 0.02); a similar inverse relation was also found for Cmax (r =-0.47; P < 0.02).
6. The interaction was variable among
individuals but reproducible within individuals. Grapefruit juice reduced the presystemic
elimination of felodipine through inhibition of primary and secondary drug metabolic
steps. The increase in felodipine AUC and Cmax was partially dependent upon the
corresponding pharmacokinetic value with water.
D.G. BAILEY, J.M.O. ARNOLD, J.R. BEND, L.T. TRAN & J.D. SPENCE