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

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