Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy subjects

Objectives: The study was conducted to investigate whether oral co-administration with citrus juices significantly affects the pharmacokinetics and/or pharmacodynamics of pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy male subjects. Grapefruit juice and orange juice, which were both commercially available, were used in this study. Methods: Sixteen healthy male Japanese subjects participated in this study and were divided into two groups for grapefruit juice and orange juice treatment. The study followed an open-labelled crossover design, comparing the effects of a single oral dose of 2 mg pranidipine taken together with 250 mi citrus juice or 250 mi water. Serum pharmacokinetics of pranidipine, adverse reactions, blood pressure, heart rate, 12-lead EGG, haematology, clinical chemistry and urinalysis were measured throughout the study. Results: For grapefruit juice, mean C-max and AUC(0-24 h) were significantly higher than those of water (P = 0.0003 and 0.0005, respectively, ANOVA) with the ratios of log transformed values being 1.50 and 1.74, respectively. There were no differences in t(max) and t(1/2) between the juice and water treatments. A significant increase in heart rate (P = 0.0240, ANOVA with repeated measurements) was observed in the juice treatment whereas there were no significant differences in systolic and diastolic blood pressure between the two treatments. For orange juice, a small decrease in mean C-max was observed compared with water (P = 0.0218, ANOVA) with the ratio being 0.86, but there was no significant difference in AUC(0-24 h) between the two treatments. No marked differences were observed in t(max) and t(1/2). Oral pranidipine administration with orange juice did not affect heart rate, systolic and diastolic blood pressures of other parameters for safety evaluation. Conclusions: Oral co-administration with grapefruit juice and pranidipine was associated with increased bioavailability and changed the pharmacodynamics of pranidipine, particularly with regard to heart rate. Orange juice intake with pranidipine did not markedly affect the pharmacokinetics and no clinically significant changes were observed in the pharmacodynamics and safety evaluation.