INDUCING PROPERTIES OF RIFAMPICIN AND RIFABUTIN FOR SELECTED ENZYME-ACTIVITIES OF THE CYTOCHROME-P-450 AND UDP-GLUCURONOSYLTRANSFERASE SUPERFAMILIES IN FEMALE RAT-LIVER

Important species differences have been reported concerning the induct ion properties of rifampicin towards enzymes of the P-450 superfamily. Mice, rabbits and humans are far more responsive than rats and guinea pigs. In the present study a strong induction of cytochrome P-450 3A- dependent enzyme activities was observed in female rat liver microsome s after high dose treatment (greater than or equal to 250 mg/kg/day fo r 9 days) with rifampicin, resulting in an up to 30-fold enhanced hydr oxylation rate of testosterone in the 2 beta-, 6 beta- and 15 beta-pos ition in vitro. Other cytochrome P-450 isozyme-selective reactions wer e not, or only marginally, affected. A steep increase in cytochrome P- 450 3A activity on a moderate elevation of the dose administered, toge ther with the previously observed lack of efficient induction with dos es below 200 mg/kg/day demonstrated that there is a threshold in enzym e induction by rifampicin. For rifabutin such a threshold was not appa rent. Induction by rifabutin showed an isoenzyme-selectivity profile s imilar to that produced by rifampicin, but the maximally achievable in duction of cytochrome P-450 3A by rifabutin was about two-fold lower c ompared with rifampicin. Rifampicin and rifabutin enhanced the glucuro nidation of l-naphthol, 4-hydroxybiphenyl and beta-estradiol by a fact or of two to three. The potential implications of the enzyme induction by rifampicin derivatives in terms of possible drug-drug interactions are discussed.