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 immediate-release 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 Cmax 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.


CONCLUSIONS
The interaction is attributed to inhibition of cytochrome 3A4-mediated first-pass metabolism. Ketoconazole 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.
Heinig
R
R
Institute of Clinical Pharmacology, Bayer AG, Wuppertal, Germany.
Adelmann
H G
HG
Ahr
G
G
D000328:Adult; D000935:Antifungal Agents / Q000737:chemistry*; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D015737:Nisoldipine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
D000935:Antifungal Agents; D002121:Calcium Channel Blockers; D015737:Nisoldipine; D007654:Ketoconazole