The Metabolism of Cimetidine in the Rat, Dog and Man

Abstract

The metabolism of metiamide (1, Scheme l), the first orally active histamine H2-receptor antagonist, has already been described (Taylor, 1973). Cimetidine (2, Scheme 1) is a new H,-receptor antagonist described by Brimblecombe et al. (1975), in which the thioureido group of metiamide (1) is replaced by a cyanoguanidino group. The present communication reports some initial studies on the metabolism of cimetidine, labelled in the 2-position of the imidazole ring with either 3H or 14C in rat, dog and man. When cimetidine was given orally to male rats, 58 % of the dose (30mg/kg) of 14C was excreted in the urine in 2411, and approx. 50% of this was unchanged cimetidine; after intravenous dosing, 71 7; of 14C was excreted in the urine, 55 % of which was unchanged compound. Similarly, female rats excreted 64% of the 14C oral dose and 73% of the intravenous dose in the urine in 24h but metabolized the compound to a lesser extent, about 74% of the urinary radioactivity being present as unchanged drug. T.1.c. and radioautography showed the presence of unchanged compound together with one major and two minor metabolites. The difference in metabolism between male and female rats was due largely to the greater conversion into the major metabolite by the male rats.

Physiologically-Based Pharmacokinetic Modeling for Drug-Drug Interactions of Procainamide and N-Acetylprocainamide with Cimetidine, an Inhibitor of rOCT2 and rMATE1, in Rats

“…The information used for the PBPK modeling of cimetidine is summarized in Table 3. Blood binding characteristics of cimetidine, including the free fraction in rat plasma (fup = 0.836) and R-value (R = 1), were obtained from the literature [56,57], on the basis of the assumption of little species difference in R-value (human R = 0.97). According to the goodness-of-fit criteria including visual inspections of fitted curves, the Akaike information criterion (AIC) and the coefficient of variation (CV), the central compartment with two peripheral compartments was considered to be appropriate for the cimetidine pharmacokinetics, and consequent parameters required for the PBPK calculation (e.g., distributional clearance, and volume of distribution for tissue compartments) were obtained using Winnonlin software.…”

PROCEEDINGS OF THE British Pharmacological Society 4th–6th April, 1979

“…for support. Cimetidine, an H2-receptor blocking drug, is well absorbed in man, rat and dog after oral dosing (Taylor & Cresswell, 1975;Burland, Duncan, Hesselbo, Mills, Sharpe, Haggie & Wyllie, 1975). However, absorption is often discontinuous and does not follow first-order kinetics.…”

“…In some experiments cimetidine sulphoxide was detected after incubation and it is possible that this may account for some of the urinary sulphoxide found after oral administration of ['4C]-cimetidine (Taylor & Cresswell, 1975 …”