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Abstract

Abstract:We investigated the effect of cytochrome P450 induction by rifampicin on the in vivo oxidative metabolism of quinidine. The pharmacokinetics of a 200 mg oral single dose quinidine were studied before and after one week of daily treatment with 600 mg rifampicin in six healthy young male volunteers. Biomarker reactions of cytochrome P450 isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. The median total apparent oral clearance and partial clearance by 3-hydroxylation of quinidine increased 9 times. The partial clearance by N-oxidation increased 6 times. The C,, and the elimination half life were reduced 3 times. No statistically significant changes were found for quinidine t , , , and renal clearance. The cortisol metabolic ratio increased 5 times, while no statistically significant effects were seen for other CYP marker reactions. The results indicate that the inductive effect of rifampicin is likely to be of clinical relevance particulary when used concomitantly with drugs metabolized by CYP3A4.Cytochome P4503A4 (CYP3A4) accounts for approximately 30% of the total human liver cytochrome content and contributes to the oxidative metabolism of a wide range of drugs. The activity of CYP3A4 varies at least 10 times among individuals (Shimada et al. 1994), and the search for a suitable biomarker reaction of CYP3A4 activity, in order to assess CYP3A4 activity on an individual basis, is intense.