Dominique Pessayre Inserm Rh

The effects of the antibiotic rifampin on microsomal drug metabolizing enzymes were investigated. On acute administration, rifampin (100 mg/kg i.p.) doubled hexobarbital sleeping time and zoxazolamine paralysis time in mice. The in vitro metabolism of zoxazolamine (0.25 mM) and 17β-estradiol (10 μM) were inhibited 50% by rifampin in concentrations of 0.4 and 0.3 mM, respectively. The inhibition of ethylmorphine N-demethylase was competitive with an apparent Ki, of 52 μM. Repeated administration of rifampin to mice (50 mg/kg i.p. daily for 6 days) increased liver weight by 20%a cytochrome P-450 (50%), NADPH cytochrome c reductase (43%,). ethylmorphine N-demethylase (85%), zoxazolamine hydroxylase (77%), benzpyrene hydroxylase (174%). and 17β-estradiol metabolism (89%). Microsomal protein (mg/g). aniline hydroxylase and p-nitrophenol glucuronyl transferase activities were unaffected.

Rat microsomal drug metabolizing enzyme activity was also inhibited after acute administration of rifampin as exemplified by an increase in hexobarbital sleeping time of 44% and a competitive inhibition of ethylmorphine N-demethylase by rifampin. The Ki, (33 μM) was close to that obtained with the mouse enzyme. The similarity in the in vivo and in vitro inhibition suggests that rifampin binds to microsomes in a similar manner in both species. Chronic administration of rifampin to rats (50 mg/kg i.p.) twice daily for six days did not lead to induction, indicating a species difference with respect to rifampin's inducing ability. Rifampin did not modify microsomal induction in rats by phenobarbital when both drugs were administered concomitantly. The mechanism responsible for the species difference and the clinical relevance of these results are discussed.

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