ABSTRACT
OBJECTIVE: To investigate the influence of oral contraceptives on cytochrome P450 3A4 (P450NF) activity. METHODS: In 23 healthy women, the pharmacokinetics of nifedipine and its main metabolite dehydronifedipine in plasma were assessed after a single oral dose, prior to and after intake of one of two oral contraceptive formulations, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). RESULTS: While the intake of two oral contraceptives for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine, mean AUC0-23.5 h and the mean Cmax values of dehydronifedipine were significantly lower in both groups tested/(24% in group A and 25% in group B). This observation may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. The activation of the same or other metabolic degradation mechanism(s) could explain this result. CONCLUSION: The investigation presented demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing ability.
PIP: The influence of combined oral contraceptives (OCs) on cytochrome P450 3A4 activity was investigated in a study of 23 healthy women. The pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in plasma were measured after a single oral dose, before and after intake of 1 or 2 OC formulations. The first contained 2 mg of dienogest and 0.03 mg of ethinyl estradiol (group A); the second contained 0.125 mg of levonorgestrel and 0.03 mg of ethinyl estradiol (group B). OC use for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine. However, the mean area-under-curve values at 0-23.5 hours after nifedipine administration were significantly lower than baseline (by 24% in group A and 25% in group B). This finding may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. Activation of the same or other metabolic degradation mechanisms could explain this finding. Assessment of its clinical importance requires a longer period of nifedipine use. This study demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing activity.