The pharmacokinetic basis for H2-antagonist drug interactions: concepts and implications

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.