Drug Interactions with Cimetidine
Drug Interactions with Cimetidine
复制标题
西咪替丁的药物相互作用
DOI：
10.2165/00003088-198207010-00002
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发表时间：
1982
影响因子：
4.5
通讯作者：
R. Gugler
中科院分区：
文献类型：
--
作者：
A. Somogyi;R. Gugler
由于西咪替丁的广泛使用（通常是不严格的），与其他药物发生相互作用的可能性相当大。在吸收研究中，苄青霉素的吸收在大多数情况下不受西咪替丁的干扰，但在I例受试者中反复出现尿排泄增加数倍，表明某些患者可能发生酸不稳定化合物的吸收增加。酮康唑的吸收减少了一半以上的西咪替丁，其水溶性差的结果，这是在酸性溶液中增强。报告了四环素的吸收结果，西咪替丁似乎不会显著改变四环素的总吸收。当胃内pH升高至3.5以上时，6名受试者中有3名的西咪替丁使阿司匹林吸收减半。西咪替丁不影响氨苄西林、复方新诺明或泼尼松龙的吸收。西咪替丁已被证明可抑制动物和人类肝脏中的各种微粒体药物代谢酶，最有可能是通过西咪替丁的咪唑环结构与细胞色素P-450的血红素部分结合。在7项研究中，西咪替丁均匀延长安替比林半衰期18 - 37%，并降低其清除率10 - 27%。西咪替丁长期给药后，华法林清除率从3.4 ml/min降至2.5 ml/min，而分布容积和消除半衰期保持不变。在治疗方案中加入西咪替丁后，稳态华法林浓度以及凝血酶原时间增加。当西咪替丁停药时，Warcin浓度和效应均恢复至西咪替丁给药前的值。在苯二氮卓类药物中，西咪替丁使地西泮、去甲地西泮和利氮卓的血浆清除率值分别降低43%、28%和63%，半衰期相应增加，而分布容积和蛋白结合率不受影响。西咪替丁和地西泮的长期治疗导致稳态地西泮浓度增加30 - 80%。相比之下，奥沙西泮和劳拉西泮的药代动力学几乎完全通过葡萄糖醛酸化而不是氧化消除，西咪替丁没有改变。西咪替丁也抑制苯妥英、茶碱和卡马西平的代谢，单剂量西咪替丁使吲哚菁绿色清除率降低23%，这被解释为肝血流量减少。普萘洛尔浓度-时间曲线下面积（口服给药）在西咪替丁给药后增加25 - 60%，普萘洛尔静脉给药后增加25%，消除半衰期、分布容积或生物利用度无变化。长期口服普萘洛尔后，西咪替丁的稳态浓度从23.2 ng/ml增加到44.9 ng/ml。与西咪替丁相比，拉贝洛尔的生物利用度几乎翻了一番，从30%增加到54%，半衰期和全身清除率没有变化。西咪替丁使氯甲噻唑的口服清除率和消除半衰期分别增加30%和50%。高肝脏清除率药物的研究并未一致显示西咪替丁诱导的全身清除率变化西咪替丁对药物代谢的作用的特点是（a）在人体内只有约20%的西咪替丁剂量被代谢，与之相比，其它抑制性药物的代谢率要大得多;（B）在1天内达到最大效应，而效应的抵消因个别相互作用药物而异;（c）对代谢的抑制程度在肝功能受损（即肝病）的患者中更为明显。然而，中和能力在26 - 41 mmol/10 ml之间的抗酸剂（铝加氢氧化镁）使西咪替丁的生物利用度降低了20 - 35%。最近的一项研究表明，70 mmol/10 ml的铝加氢氧化镁抗酸剂不影响西咪替丁的生物利用度。所用的抗酸制剂与其他制剂的不同之处在于氢氧化铝含量的不成比例增加。甲氧氯普胺和丙胺太林也使西咪替丁的吸收平均减少20%，表明胃排空对西咪替丁吸收的重要性。苯巴比妥给药超过3周导致西咪替丁血浆清除率增加18%，这主要是由于非肾清除率增加，但也可能部分是由于西咪替丁吸收减少。临床上重要的相互作用主要表现在治疗指数较窄的药物（如苯妥英、华法林、茶碱）中。这种相互作用导致较高的稳态血药浓度，因此增加了副作用和毒性的发生率。当需要与西咪替丁同时给药时，通过仔细监测和调整在肝脏中经历I期代谢解毒的药物的剂量，可以避免这种相互作用的不良反应。
SummaryBecause of widespread (and often uncritical) use of Cimetidine, there is considerable potential for interactions to occur with other drugs.In studies on absorption, benzylpenicillin absorption was not disturbed by Cimetidine in most cases, but a several-fold increase in urinary excretion occurred repeatedly in I subject, indicating that increased absorption of acid-labile compounds may occur in some patients. The absorption of ketoconazole was reduced by more than half with Cimetidine, a consequence of its poor water solubility which is enhanced in acid solution. Conflicting results are reported with tetracycline, the overall absorption of which does not appear to be significantly altered by Cimetidine. Aspirin absorption was halved by Cimetidine in 3 of 6 subjects, when the intragastric pH was raised above 3.5. Cimetidine did not affect the absorption of ampicillin, co-trimoxazole or prednisolone.Cimetidine has been shown to inhibit various microsomal drug-metabolising enzymes in animal as well as human liver, most likely through the binding of the imidazole ring structure of Cimetidine to the haeme moiety of cytochrome P-450. In 7 studies, Cimetidine uniformly prolonged antipyrine half-life by 18 to 37% and reduced its clearance by 10 to 27%. After chronic dosing with Cimetidine, warfarin clearance was reduced from 3.4 to 2.5ml/min, whilst the volume of distribution and elimination half-life remained unchanged. Steady-state warfarin concentrations, as well as Prothrombin times, increased upon addition of Cimetidine to the treatment regimen. Warfarin concentration and effect both returned to pre-Cimetidine values when Cimetidine was withdrawn. Amongst the benzodiazepines, diazepam, desmethyldiazepam and chlordiazepoxide plasma clearance values were reduced by Cimetidine by 43, 28 and 63 %, respectively, and half-lives increased accordingly, while volumes of distribution and protein binding were not affected. Long term treatment with Cimetidine and diazepam resulted in a 30 to 80% increase in steady-state diazepam concentrations. In contrast, the pharmacokinetics of oxazepam and lorazepam, which are eliminated almost entirely by glucuronidation and not oxidation, were not altered by Cimetidine. Cimetidine also inhibits the metabolism of phenytoin, theophylline and carbamazepine.A single dose of Cimetidine decreased indocyanine green clearance by 23%, which was interpreted as a reduction in hepatic blood flow. The area below the Propranolol concentration-time curve (oral administration) was increased by between 25 and 60 % with Cimetidine and by 25 % after intravenous administration of Propranolol, with no change in elimination half-life, volume of distribution or bioavailability. With chronic oral Propranolol dosing, Cimetidine increased the steady-state concentration from 23.2 to 44.9ng/ml. The bioavailability of labetalol almost doubled from 30 to 54 % with Cimetidine, with no change in half-life and systemic clearance. The oral clearance and elimination half-life of chlormethiazole was increased by 30 and 50%, respectively, by Cimetidine. Studies with high hepatic clearance drugs have not consistently shown cimetidine-induced changes in systemic clearance (liver blood flow dependent), but oral clearance increased in all cases, consistent with inhibition of drug metabolism.Peculiarities of Cimetidine effect on drug metabolism are (a) only about 20% of a Cimetidine dose is metabolised in man, as compared with a much larger fraction with other inhibitory drugs; (b) the maximum effect attained occurs within I day whereas offset of effect varies with individual interacting drugs; (c) the degree of inhibition of metabolism is much more pronounced in patients with already impaired liver function (i.e. liver disease).Antacids of a weak neutralising capacity (10 to 15mmol/dose) did not influence the absorption of Cimetidine. However, antacids (aluminium plus magnesium hydroxide) with a neutralising capacity between 26 and 41 mmol/10ml reduced the bioavailability of Cimetidine by 20 to 35%. A recent study with an aluminium plus magnesium hydroxide antacid of 70mmol/10ml did not affect Cimetidine bioavailability. The antacid preparation used differed from others by a disproportionate increase in the aluminium hydroxide content. Metoclopramide and propantheline also reduced the absorption of Cimetidine by an average of 20 %, indicating the importance of gastric emptying for Cimetidine absorption. Phenobarbitone administration over 3 weeks led to an increase in Cimetidine plasma clearance by 18%, mainly due to an increase in the non-renal clearance, but probably also partially due to a reduction in Cimetidine absorption.The most important clinical consequences of interactions with Cimetidine primarily involve inhibition of drug metabolism. Clinically important interactions are predominantly manifested in those drugs which have a narrow therapeutic index (e.g. Phenytoin, warfarin, theophylline). The interaction leads to higher steady-state blood concentrations and hence increases the incidence of side effects and toxicity. Adverse effects of such interactions can be avoided by careful monitoring and adjustment of dosage for those drugs which undergo phase I metabolic detoxification in the liver when it is necessary to administer such drugs concomitantly with Cimetidine.
西咪替丁会损害硝西泮的清除率。
影响因子：
6.7
作者：
Ochs,HR;Greenblatt,DJ;Gugler,R;Müntefering,G;Locniskar,A;Abernethy,DR
通讯作者：
Abernethy,DR
西咪替丁减少肝血流量和普萘洛尔代谢。
DOI：
10.1056/nejm198103193041202
发表时间：
1981
期刊：
The New England journal of medicine
影响因子：
--
作者：
Feely,J;Wilkinson,GR;Wood,AJ
通讯作者：
Wood,AJ