The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine

Objective: The primary aim of the present study was to investigate the effe ct of ketoconazole on the pharmacokinetics of nisoldipine. Methods: A singl e dose of nisoldipine 5 mg immediaterelease tablet was administered either alone or in combination with ketoconazole 200 mg (4 days pretreatment and c oncomitant administration) in a randomized crossover trial in seven healthy male Caucasian volunteers. Plasma concentration-versus-time profiles of ni soldipine and its metabolite M9 were determined. Results: Pre-treatment wit h and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold, increase in mean AUC and C-max of nisoldipine, respectively, compa red with treatment with nisoldipine 5 mg alone. The ketoconazole-induced in crease in plasma concentration of the metabolite M9 was of similar magnitud e. Conclusion: The interaction is attributed to inhibition of cytochrome 3A 4-mediated first-pass metabolism. Keto-conazole and other antifungal drugs of the substituted imidazole type as well as other potent inhibitors of cyt ochrome 3A4 should not be used concomitantly with nisoldipine.