Dimova S, Stoytchev T
Department of Drug Toxicology, Bulgarian Academy of Sciences, Sofia.
Eur J Drug Metab Pharmacokinet. 1994 Oct-Dec;19(4):311-7. doi: 10.1007/BF03188857.
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.
在雄性白化病小鼠中研究了利福平对乙酰氨基酚的毒性、镇痛作用及药代动力学的影响。重复给予利福平（每天腹腔注射50mg/kg，共6天）可缩短己巴比妥睡眠时间，并增加肝脏重量、微粒体细胞色素P-450和血红素含量、NADPH-细胞色素c还原酶及乙基吗啡-N-脱甲基酶活性。苯胺羟化酶活性降低，对硝基苯酚的葡萄糖醛酸化未受影响。利福平预处理既未改变乙酰氨基酚的半数致死量，也未改变肝脏谷胱甘肽水平，以及由乙酰氨基酚毒性剂量（737mg/kg口服）引起的谷胱甘肽耗竭。这表明利福平对肝脏中形成的乙酰氨基酚毒性代谢产物的量没有影响。利福平降低了小鼠中乙酰氨基酚的镇痛作用。利福平降低了乙酰氨基酚的Cmax、半衰期（half-time）、平均滞留时间（MRT）和药时曲线下面积（AUC），并加速了其清除。乙酰氨基酚葡萄糖醛酸苷和硫酸乙酰氨基酚的血浆浓度升高。据推测，利福平降低乙酰氨基酚镇痛作用的最可能机制是加速了乙酰氨基酚的消除。
