Influence of rifampicin on the toxicity and the analgesic effect of acetaminophen.
The influence of rifampicin on the toxicity, analgesic effect and pharmacokinetics of acetaminophen was studied in male albino mice. Repeated administration of rifampicin (50 mg/kg i.p. daily for 6 days) shortened hexobarbital sleeping time and increased liver weight, microsomal cytochrome P-450 and heme contents, NADPH-cytochrome c reductase and ethylmorphine-N-demethylase activities. Aniline hydroxylase activity was decreased and glucuronidation of p-nitrophenol was unaffected. Rifampicin pretreatment changed neither the LD50 of acetaminophen nor the hepatic glutathione level nor the glutathione depletion provoked by the toxic dose of acetaminophen (737 mg/kg p.o.). This suggests that rifampicin has no influence on the amount of acetaminophen toxic metabolites formed in the liver. Rifampicin decreased the acetaminophen analgesic effect in mice. Rifampicin decreased the Cmax, the half-time, the MRT and the AUC of acetaminophen and accelerated its clearance. The plasma concentration of acetaminophen glucuronide and acetaminophen sulfate was increased. It is assumed that the most probable mechanism by which rifampicin decreases acetaminophen analgesia is the accelerated acetaminophen elimination.
Dimova
S
S
Department of Drug Toxicology, Bulgarian Academy of Sciences, Sofia.
Stoytchev
T
T
D000082:Acetaminophen / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology*
D000082:Acetaminophen; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; D005978:Glutathione; D012293:Rifampin