Powell J R, Donn K H
J Clin Gastroenterol. 1983;5 Suppl 1:95-113. doi: 10.1097/00004836-198312001-00010.
In 1978, less than two years after its release, published reports indicated that cimetidine caused an increased prothrombin time in patients receiving warfarin. It has since been established that cimetidine inhibits the hepatic metabolism of at least 15 other drugs. The time course for the interaction is rapid with the onset and termination detectable within the first day of starting or stopping cimetidine. In vitro and clinical data indicate that the interaction is dependent upon the cimetidine dose or plasma concentration, but its limits are not well defined. Cimetidine inhibits the metabolism of drugs that are primarily eliminated by the hepatic mixed-function oxidase, microsomal enzymes. The degree to which cimetidine decreases drug clearance is dependent upon the fraction of drug eliminated by the inhibited metabolic routes, the route of administration for high hepatic extraction drugs, and the patient's characteristics. Cimetidine decreases the clearance of various drugs from 20-60%. The interpatient variability in the effects of cimetidine for any given drug can be considerable. Since cimetidine and ranitidine have been reported to decrease indocyanine green clearance, it has been assumed that H2-antagonists decrease functional hepatic blood flow. However, there is direct and indirect evidence indicating there is not a significant effect on liver blood flow. At similar therapeutic doses, ranitidine does not decrease the clearance of theophylline, phenytoin, diazepam, propranolol, ethanol, antipyrine, and aminopyrine. Ranitidine does not alter the prothrombin time in subjects receiving warfarin. Differences between cimetidine and ranitidine on drug metabolism appear to exist both because the cytochrome P-450 binding affinity for ranitidine is about 10 times lower than cimetidine and because the daily ranitidine dose is 1/4 that of cimetidine. The imidazole ring and lipophilicity of cimetidine are characteristics that favor inhibition of drug metabolism. Since both cimetidine and ranitidine change the gastric pH and fluid volume, there is the potential for altering drug absorption. Drug distribution does not appear to be influenced by either agent. Although neither cimetidine nor ranitidine significantly alters the glomerular filtration rate, their influence on renal drug elimination is not well characterized. The numerous case reports of therapeutic failure primarily from drug toxicity are basically due to cimetidine inhibition of metabolism. This cimetidine effect (and lack of ranitidine effect) may help explain differences in the adverse effect profiles between cimetidine and ranitidine and may be important for a number of uninvestigated drugs.
1978年，西咪替丁上市不到两年，已发表的报告表明，它会使接受华法林治疗的患者凝血酶原时间延长。此后已证实，西咪替丁会抑制至少15种其他药物的肝脏代谢。相互作用的时间过程很快，在开始或停用西咪替丁的第一天内即可检测到其起效和终止。体外和临床数据表明，这种相互作用取决于西咪替丁的剂量或血浆浓度，但其限度尚未明确界定。西咪替丁抑制主要通过肝脏混合功能氧化酶（微粒体酶）消除的药物的代谢。西咪替丁降低药物清除率的程度取决于被抑制代谢途径消除的药物分数、高肝脏摄取药物的给药途径以及患者的特征。西咪替丁可使各种药物的清除率降低20%至60%。对于任何一种给定药物，西咪替丁作用的患者间变异性可能相当大。由于据报道西咪替丁和雷尼替丁会降低吲哚菁绿清除率，因此人们认为H2拮抗剂会降低肝脏功能性血流量。然而，有直接和间接证据表明其对肝血流量并无显著影响。在相似的治疗剂量下，雷尼替丁不会降低茶碱、苯妥英、地西泮、普萘洛尔、乙醇、安替比林和氨基比林的清除率。雷尼替丁不会改变接受华法林治疗患者的凝血酶原时间。西咪替丁和雷尼替丁在药物代谢方面的差异似乎既存在于细胞色素P - 450对雷尼替丁的结合亲和力约比西咪替丁低10倍，也存在于雷尼替丁的每日剂量是西咪替丁的1/4。西咪替丁的咪唑环和亲脂性是有利于抑制药物代谢的特性。由于西咪替丁和雷尼替丁都会改变胃的pH值和液体量，因此存在改变药物吸收的可能性。药物分布似乎不受这两种药物中任何一种的影响。虽然西咪替丁和雷尼替丁均未显著改变肾小球滤过率，但它们对肾脏药物消除的影响尚未明确。众多主要因药物毒性导致治疗失败的病例报告基本上是由于西咪替丁对代谢的抑制作用。西咪替丁的这种作用（以及雷尼替丁无此作用）可能有助于解释西咪替丁和雷尼替丁在不良反应谱方面的差异，并且可能对许多未研究的药物很重要。
