SELECTIVE-INHIBITION OF ACETAMINOPHEN OXIDATION AND TOXICITY BY CIMETIDINE AND OTHER HISTAMINE H2-RECEPTOR ANTAGONISTS INVIVO AND INVITRO IN THE RAT AND IN MAN
SELECTIVE-INHIBITION OF ACETAMINOPHEN OXIDATION AND TOXICITY BY CIMETIDINE AND OTHER HISTAMINE H2-RECEPTOR ANTAGONISTS INVIVO AND INVITRO IN THE RAT AND IN MAN
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DOI：
10.1172/jci111223
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发表时间：
1984-01-01
影响因子：
15.9
通讯作者：
SPEEG, KV
中科院分区：
文献类型：
--
作者：
MITCHELL, MC;SCHENKER, S;SPEEG, KV
扑热息痛引起的肝毒性是由于肝酶将扑热息痛氧化成一种有毒的亲电中间体。扑热息痛通常在与葡萄糖醛酸和硫酸盐偶联成无毒的衍生物后被消除。西咪替丁可抑制多种药物的肝脏氧化，保护对乙酰氨基酚诱导的大鼠肝坏死。确定了西咪替丁减轻对乙酰氨基酚诱导的肝坏死的机制，并确定了在人体内是否也抑制了对乙酰氨基酚的反应性代谢物(S)的形成。在体内，西咪替丁预处理使[~3H]对乙酰氨基酚与肝脏的共价结合从552.+-降低。23.8至170+-对乙酰氨基酚染毒后2 h，31.6nmol/g蛋白(P<；0.05)。西咪替丁预处理也能显著降低肝脏谷胱甘肽耗竭率。西咪替丁和甲硫胺对对乙酰氨基酚的体外氧化均有剂量依赖性抑制作用；雷尼替丁和西咪替丁亚砜对对乙酰氨基酚氧化的抑制作用较弱。西咪替丁和甲硫胺对对乙酰氨基酚氧化的抑制作用主要与KI为130.+-竞争。16和200。+-分别为50µm。西咪替丁对对乙酰氨基酚葡萄糖醛酸化反应的抑制作用最小，Ki为1.39。0.23毫米。用人肝微粒体作为酶的来源也得到了类似的结果。在与微粒子和NADPH孵育时，西咪替丁也以剂量相关的方式降低了对乙酰氨基酚对人类淋巴细胞的毒性。西咪替丁每隔6h给药300 mg时，在正常受试者体内研究了对乙酰氨基酚消除的药代动力学过程，西咪替丁对对乙酰氨基酚氧化(潜在毒性)代谢物的部分清除量的降低幅度大于其结合代谢物。这一发现证实了西咪替丁在人类和动物中是对乙酰氨基酚氧化为反应性代谢物的相对选择性抑制剂的假设。考虑到以前的研究结果表明，醋氨酚中毒动物的存活率提高和肝毒性降低，本研究结果为评估西咪替丁治疗人类过量醋氨酚的可能益处提供了合理的基础。
Acetaminophen-induced hepatotoxicity results from hepatic enzymatic oxidation of acetaminophen to a toxic, electrophilic intermediate. Acetaminophen is ordinarily eliminated after conjugation with glucuronic acid and sulfate to nontoxic derivatives. Cimetidine inhibits the hepatic oxidation of a number of drugs and protects rats from acetaminophen-induced hepatic necrosis. The mechanism by which cimetidine reduced acetaminophen-induced hepatic necrosis was defined, and whether inhibition of formation of the reactive metabolite(s) of acetaminophen occurred also in man was determined.In vivo cimetidine pretreatment decreased covalent binding of [3H]acetaminophen to the liver from 552 .+-. 23.8 to 170 .+-. 31.6 nmol/g protein 2 h after a toxic dose of acetaminophen in 3-methylcholanthrene pretreated rats (P < 0.05). Cimetidine pretreatment also significantly reduced the rate of hepatic glutathione depletion. Both cimetidine and metiamide produced dose-dependent inhibition of acetaminophen oxidation in vitro; inhibition by ranitidine and cimetidine sulfoxide was quantitatively less. Inhibition of acetaminophen oxidation by cimetidine and metiamide was primarily competitive with an Ki of 130 .+-. 16 and 200 .+-. 50 .mu.M, respectively. Cimetidine inhibited acetaminophen glucuronidation minimally with a Ki of 1.39 .+-. 0.23 mM. Similar results were obtained using human liver microsomes as a source of enzymes. In a dose-related fashion, cimetidine also reduced acetaminophen-induced toxicity to human lymphocytes when incubated with microsomes and NADPH. Pharmacokinetics of acetaminophen elimination were studied in normal volunteers with and without co-administration of cimetidine 300 mg every 6 h. In normal volunteers, cimetidine decreased the fractional clearance of the oxidized (potentially toxic) metabolites of acetaminophen more than the conjugated metabolites. This finding confirmed the hypothesis that cimetidine is a relatively selective inhibitor of the oxidation of acetaminophen to reactive metabolites in man as well as in animals. When considered together with the results of previous studies showing improved survival and decreased hepatotoxicity in acetaminophen-poisoned animals, the present results provide a rational basis for assessing possible benefits of cimetidine treatment of acetaminophen overdoses in man.