Abernethy D R, Greenblatt D J, Divoll M, Ameer B, Shader R I
J Pharmacol Exp Ther. 1983 Mar;224(3):508-13.
Fourteen healthy volunteers received a single i.v. dose of antipyrine (1.2 g) on two occasions, once before and once during cimetidine treatment (300 mg every 6 hr). In a similar manner, 8 subjects received diazepam (10 mg), 11 subjects received acetaminophen (650 mg) and 8 subjects received lorazepam (2 mg), all by the i.v. route, once before and once during cimetidine coadministration. Pharmacokinetic analysis indicated increased antipyrine elimination T1/2 during cimetidine treatment (16.7 vs. 10.9 hr; P less than .001) on the basis of decreased total metabolic clearance (0.46 vs. 0.72 ml/min/kg; P less than .001). Likewise, diazepam T1/2 was increased (58 vs. 39 hr; P less than .01) during cimetidine treatment due to decreased total metabolic clearance (0.42 vs. 0.30 ml/min/kg; P less than .01). In contrast, cimetidine did not alter T1/2 or the clearance of lorazepam (T1/2, 16.8 vs. 15.3 hr; clearance, 1.03 vs 1.07 ml/min/kg) or acetaminophen (T1/2, 2.66 vs. 2.60 hr; clearance, 4.8 vs. 4.5 ml/min/kg), both drugs which undergo conjugative biotransformation. In an animal model used to assess the effect of cimetidine on acetaminophen toxicity, the LD50 of acetaminophen alone in Charles River CD-1 mice was 480 mg/kg (95% confidence interval: 436-528 mg/kg). With simultaneous 75 mg/kg of cimetidine treatment, the LD50 for acetaminophen was significantly increased (P less than .05) to 1020 mg/kg (95% confidence interval: 962-1081 mg/kg). Thus, cimetidine slows the metabolic clearance of antipyrine and diazepam, drugs biotransformed by hepatic oxidation, but does not alter the kinetics of acetaminophen or lorazepam, both metabolized by conjugation. Cimetidine may decrease the toxicity of high-dose acetaminophen by preventing formation of the hepatotoxic oxidative metabolites, although having no effect on conjugation of acetaminophen which yields nontoxic metabolites that are subsequently cleared from the body.
14名健康志愿者分两次接受了单次静脉注射安替比林（1.2克），一次在西咪替丁治疗前（每6小时300毫克），一次在西咪替丁治疗期间。同样，8名受试者静脉注射地西泮（10毫克），11名受试者静脉注射对乙酰氨基酚（650毫克），8名受试者静脉注射劳拉西泮（2毫克），均在西咪替丁联合用药前和用药期间各进行一次。药代动力学分析表明，在西咪替丁治疗期间，安替比林的消除半衰期延长（16.7小时对10.9小时；P<0.001），这是基于总代谢清除率降低（0.46毫升/分钟/千克对0.72毫升/分钟/千克；P<0.001）。同样，在西咪替丁治疗期间，地西泮的半衰期延长（58小时对39小时；P<0.01），原因是总代谢清除率降低（0.42毫升/分钟/千克对0.30毫升/分钟/千克；P<0.01）。相比之下，西咪替丁并未改变劳拉西泮（半衰期，16.8小时对15.3小时；清除率，1.03毫升/分钟/千克对1.07毫升/分钟/千克）或对乙酰氨基酚（半衰期，2.66小时对2.60小时；清除率，4.8毫升/分钟/千克对4.5毫升/分钟/千克）的半衰期或清除率，这两种药物均通过结合性生物转化代谢。在用于评估西咪替丁对乙酰氨基酚毒性影响的动物模型中，查尔斯河CD-1小鼠单独使用乙酰氨基酚的半数致死量为480毫克/千克（95%置信区间：436-528毫克/千克）。同时给予75毫克/千克西咪替丁治疗时，乙酰氨基酚的半数致死量显著增加（P<0.05）至1020毫克/千克（95%置信区间：962-1081毫克/千克）。因此，西咪替丁减缓了安替比林和地西泮的代谢清除率，这两种药物通过肝脏氧化进行生物转化，但并未改变通过结合代谢的对乙酰氨基酚或劳拉西泮的动力学。西咪替丁可能通过阻止肝毒性氧化代谢产物的形成来降低高剂量对乙酰氨基酚的毒性，尽管对产生无毒代谢产物并随后从体内清除的对乙酰氨基酚结合过程没有影响。
