Pharmacokinetic Interactions of Cimetidine 1987

Abstract

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.(ABSTRACT TRUNCATED AT 400 WORDS)

Lack of effect of cimetidine on the pharmacokinetics of R(−)− and S(+)‐ ibuprofen.

“…For an orally administered drug which is cleared predominantly by hepatic metabolism, AUC is related to the dose administered, the fraction of administered dose which is absorbed from the gut into the hepatic portal vein (FG), the plasma unbound fraction of the drug (fu) and its intrinsic clearance (CLint) (Somogyi & Muirhead, 1987). Previous investigations with ibuprofen indicated that a large fraction of an orally administered dose is recovered in urine as unchanged drug and metabolites (Lockwood & Wagner, 1982;Mills et al, 1973).…”

“…Because ibuprofen's spectrum of adverse reactions includes gastrointestinal side-effects (Fowler et al 1980), concurrent administration with anti-ulcer drugs, such as the histamine H2-receptor antagonist cimetidine, is not uncommon. Cimetidine is known to interact with a large number of drugs by inhibiting their oxidative metabolism (Somogyi & Muirhead, 1987). Because oxidative biotransformation plays such an important role in the disposition of ibuprofen, it seems a likely candidate for a pharmacokinetic interaction with cimetidine.…”

Lack of effect of cimetidine on the pharmacokinetics of bupivacaine in healthy subjects.

“…Cimetidine has also been shown to decrease the renal clearance of ranitidine, metformin, triamterene and flecainide (Somogyi & Muirhead, 1987) or of procainamide and its active metabolite N-acetylprocainamide (Somogyi et al, 1983), by competing with them for the active transport system for bases. In the present study we found no suggestion of excretory interaction between cimetidine and the parent drug or its two metabolites.…”

“…It is also used for anaesthetic premedication to lower the incidence of the acid aspiration syndrome (Dundee et al, 1981;Manchikanti et al, 1982). However, cimetidine has also been shown to inhibit the elimination of many other drugs (Somogyi & Muirhead, 1987), including lignocaine, which is structurally related to bupivacaine (Kim & Tasch, 1986;Feely et al, 1982;Knapp et al, 1983;Bauer et al, 1984). All of the amide local anaesthetic agents are metabolized primarily in the liver (Covino, 1984) and cimetidine is capable of impairing drug oxidation at this site.…”

Effects of H2‐receptor antagonists on ethanol metabolism in Japanese volunteers.

“…Cimetidine, a histamine H2-receptor antagonist, is a competitive inhibitor of the hepatic cytochrome P-450 mixed function oxidase system (Somogyi & Gugler, 1982;Somogyi & Muirhead, 1987). Ranitidine and famotidine do not inhibit this system (Cate et al, 1986;Locniskar et al, 1986).…”