Pharmacokinetic Interactions of Cimetidine 1987

Summary

The number of studies on drug interactions with Cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations.

Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, Ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active. Cimetidine does not alter plasma protein binding of other drugs, but reduces the volumes of distribution of labetolol, lignocaine (lidocaine), Imipramine and pethidine (meperidine) by unknown mechanisms. Cimetidine increases the plasma concentrations of drugs in a wide range of therapeutic classes.

A number of physiological, pathological and drug-related factors alter the degree of inhibition of hepatic drug clearance by cimetidine. In certain patients with already depressed drug clearance (e.g. the elderly, the cirrhotic), cimetidine will further decrease drug clearance to a potentially dangerous extent. This reduction in drug clearance is greater following enzyme induction by rifampicin or phenytoin or in smokers, although findings in the latter group have been inconsistent. Cimetidine will not fully attenuate the induction of drug metabolism by the above agents.

The degree of inhibition of drug metabolism by cimetidine is of the order of 10 to 20% with a daily dosage of 300 to 400mg, 20 to 30% with 400 to 800mg, 30 to 40% with 800 to 1600mg: with daily dosages greater than 2000mg, the inhibition is between 40 and 50%, depending upon the substrate used. The onset of inhibition is rapid: maximum inhibition occurs 24 hours after starting cimetidine, and is maintained for at least 30 days if cimetidine is continued. The recovery rate is also rapid and clearance rates return to baseline 2 to 3 days after stopping cimetidine, depending on the half-life of the interacting drug; in the case of warfarin, plasma concentrations will not return to the precimetidine level for at least 7 days.

Because of the large number of drugs which can potentially interact with cimetidine, the physician should suspect a drug interaction when an abnormal response is encountered in any patient coprescribed cimetidine. Toxicity may occur for drugs with a narrow therapeutic index, e.g. theophylline, Phenytoin, warfarin and the majority of the antiarrhythmic, antidepressant and antipsychotic drugs for which clinical evidence of the drug interactions has been reported. These patients can be managed by: (a) reducing the dose of the interacting drug; (b) selecting a drug of similar therapeutic efficacy that does not interact with cimetidine; or (c) selecting other antiulcer drugs which do not interact. The need for cimetidine or other antiulcer therapy should also be assessed.

Although cimetidine interacts with a large number of drugs, reports of incidents of drug toxicity are uncommon. This may be due to the fact that physicians are well aware of those drugs with a narrow therapeutic index which interact clinically with cimetidine and have taken appropriate action, or the fact that the majority of drugs have a wide therapeutic index, so that a 50% increase in plasma concentration would not be deleterious to the patient.