GRAPEFRUIT JUICE-FELODIPINE INTERACTION - REPRODUCIBILITY AND CHARACTERIZATION WITH THE EXTENDED-RELEASE DRUG FORMULATION

1 Felodipine 10 mg extended release was administered with 250 mi regul ar-strength grapefruit juice or water in a randomized crossover manner followed by a second grapefruit juice treatment in 12 healthy men. Th e pharmacokinetics of felodipine and primary oxidative metabolite, deh ydrofelodipine, were evaluated. 2 Initial grapefruit juice treatment i ncreased felodipine AUC (mean +/- s.d.; 56.6 +/- 21.9 vs 28.1 +/- 11.5 ng ml(-1) h; P < 0.001) and C-max (8.1 +/- 2.5 vs 3.3 +/- 1.2 ng ml(- 1) P < 0.001) compared with water. Felodipine t(max) (median; 2.8 vs 3 .0 h) and t(1/2) (7.3 +/- 3.7 vs 6.9 +/- 3.6 h) were not altered. 3 Re administration of felodipine with grapefruit juice produced mean felod ipine AUC (61.5 +/- 32.2 ng ml(-1) h) and C-max (8.4 +/- 4.8 ng ml(-1) ) which were similar to the initial grapefruit juice treatment 1-3 wee ks previously. Felodipine AUC (r = 0.73, P < 0.01) and C-max (r = 0.69 , P < 0.02) correlated between grapefruit juice treatments among indiv iduals. 4 The % increase in felodipine AUC with the initial grapefruit juice treatment compared with water correlated with the % increase in felodipine C-max among individuals (r = 0.80, P < 0.01). Dehydrofelod ipine AUC (74.7 +/- 28.7 vs 48.5 +/- 16.3 ng ml(-1) h; P < 0.01) and C -max (12.1 +/- 2.9 vs 7.9 +/- 2.6 ng ml(-1); P < 0.01) were augmented with grapefruit juice compared with water, The ratios of dehydrofelodi pine/felodipine for AUC (1.35 +/- 0.26 vs 1.78 +/- 0.23; P < 0.001) an d at felodipine C-max (1.55 +/- 0.35 vs 2.33 +/- 0.29; P < 0.001) were reduced. 5 There was a negative correlation between felodipine AUC wi th water and the % increase in AUC among individuals with data combine d from both grapefruit juice treatments (r = -0.47; P < 0.02); a simil ar inverse relation was also found for C-max (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 C-max was partially dependen t upon the corresponding pharmacokinetic value with water.