INFLUENCE OF RIFAMPICIN ON THE TOXICITY AND THE ANALGESIC EFFECT OF ACETAMINOPHEN

The influence of rifampicin on the toxicity, analgesic effect and phar macokinetics of acetaminophen was studied in male albino mice. Repeate d administration of rifampicin (50 mg/kg i.p. daily for 6 days) shorte ned hexobarbital sleeping time and increased liver weight, microsomal cytochrome P-450 and heme contents, NADPH-cytochrome c reductase and e thylmorphine-N-demethylase activities. Aniline hydroxylase activity wa s decreased and glucuronidation of p-nitrophenol was unaffected. Rifam picin pretreatment changed neither the LD(50) of acetaminophen nor the hepatic glutathione level nor the glutathione depletion provoked by t he toxic dose of acetaminophen (737 mg/kg p.o.). This suggests that ri fampicin has no influence on the amount of acetaminophen toxic metabol ites formed in the liver. Rifampicin decreased the acetaminophen analg esic effect in mice. Rifampicin decreased the C-max, the half-time, th e MRT and the AUC of acetaminophen and accelerated its clearance. The plasma concentration of acetaminophen glucuronide and acetaminophen su lfate was increased. It is assumed that the most probable mechanism by which rifampicin decreases acetaminophen analgesia is the accelerated acetaminophen elimination.