The effects of H 2 receptor antagonists on hepatic microsomal drug metabolism and fine morphology of rat liver

Abstract

The study is concerned with the effects of cimetidine(C), ranitidine(R) and oxmetidine(O) on rat liver cells, in order to compare the effects of increasing amounts of the drugs on various metabolic.pathways and on hepatocyte morphology, and their relationship with the drug structure, namely the presence of an imidazole or furan ring.In vitro, an inhibition of ethylmorphine N-demethylase(E-DM)(60%) and of aniline hydroxylase(A OH)(20%) was observed when either C or R were added at a concentration higher than 0.5 mm to microsomes from untreated rats. Microsomes from phenobarbital or 3-methylcholanthrene-pretreated animals showed a 30 to 40% inhibition of E-DM (mixed type inhibition).In vivo, administration of a single dose (475 μM/kg) of R was followed by an inhibition of E-DM activity, significantly less pronounced (p<0.05) than following an equimolar amount of C, whereas O did not alter the enzymatic acitvity. The amount of cytochrome P-450 and the activities of NADPH cytochrome c reductase and of A OH were substantially unaffected. No changes of smooth endoplasmic reticulum or of other liver cell organelles were observed by electron microscopy. These findings demonstrate that both in vivo and in vitro E-DM appears as the more sensitive among the pathways considered. Moreover the data support the view that the mere presence of the imidazole ring does not account for the inhibitory effect of H 2 antagonists. The three histamine H 2 receptor antagonists ranitidine(R), cimetidine(C) and oxmetidine(O) show different structures and pharmacokinetics. C and O have the same imidazole ring and different side chains, while R has a furan ring. All 3 drugs undergo first pass hepatic metabolism and their bioavailability ranges from 40% (O) to 60% (C) of the administered dose. C and R are excreted by glomerular filtration mainly unchanged but a significant part is metabolized. The clearance is very fast for both drugs, with half lives almost doubled in anuric patients. O is mainly metabolized by glucuronide conjugation in the liver and then excreted in urine and bile. Its liposolubility is much greater than that of the other 2 drugs ( Walkenstein et al 1978, Bell et al 1980, Gugler Somogyi and Bergmann 1981, Gugler Somogyi and Rohener 1982) (tab 1). [Display omitted] C has been clearly shown to be an inhibitor of hepatic microsomal drug metabolism in clinical studies, in experimental animals and in vitro systems ( Serlin et al 1979, Rendic et al 1979, Klotz and Reimann 1980, Puurunen Sotaniemi and Pelkonen 1980, Henry et al 1980, Pelkonen and Puurunen 1980, Knodell et al 1982, Speeg et al 1982, Mavier et al 1983); such an action, of rapid onset and reversibility, is potentially dangerous when C is concurrently administered with drugs of low therapeutic index actively metabolized by the microsomal mixed-function oxidase system. The inhibitory action of C has been attributed to the presence of an imidazole ring, for a number of drugs belonging to the substituted imidazole class behave as inhibitors of microsomal oxidation ( Wilkinson Hetnarsky and Hicks 1974). Hepatic phase II reactions are unimpaired by C ( Pathwardan et al 1980). In man, at therapeutic doses, R has no inhibitory effect on the metabolic clearance of model drugs such as antipyrine or aminopyrine ( Henry et al 1980, Staiger et al 1980). Controversial results have been obtained in laboratory animals and in in vitro systems. Hexobarbital and pentobarbital sleeping time ( Bell et al 1980, Mavier et al 1983), meperidine demethylase, ethylmorphine demethylase and pentobarbital hydroxylase activities were unchanged ( Knodell et al 1982, Mavier et al 1983). Aminopyrine demethylase activity appeared reduced ( Speeg et al 1982) or unchanged (Mavier et al 1983), aniline hydroxylase activity was reduced (Mavier et al 1983). No binding ( Knodell et al 1982) or a low affinity interaction producing a type II spectral change of cytochrome P-450 ( Speeg et al 1982) was observed. As a rule, when shown, the inhibitory action of R on microsomal drug metabolism was much lowar compared to C. Until now no inhibitory effect has been shown for O in humans and rats, however this aspect has not been extensively studied ( Mihaly et al 1982, Henry Kitchingman and Langman 1981). In this study we have compared the effects of pharmacological doses of R on rat microsomal drug metabolism with those of C or O, both in vitro and after in vivo administration of the 3 drugs.