title: Effect of five structurally diverse H2-receptor antagonists on drug metabolism.
abstract: Some H2-receptor antagonists can interact with the biotransformation of other drugs. This is due to their binding to cytochrome P-450. We tested the in vitro effects of 5 different H2-receptor antagonists cimetidine (C), oxmetidine (O), ranitidine (R), famotidine (F) and nizatidine (N) on arylhydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase and 7-ethoxy-resorufin-O-deethylase activity using liver microsomes from man as well as from untreated, phenobarbital and 3-methylcholanthrene treated rats. In addition their binding to human microsomal cytochrome P-450 was evaluated. The in vivo effects of these antagonists were investigated on the hepatic elimination of diazepam in healthy volunteers. In vitro O was found to be the most effective inhibitor of the enzyme activities studied. C showed a clear inhibitory effect only with rat liver microsomes whereas the remaining drugs were more than 10 times less potent. The binding affinities of these antagonists showed a similar tendency: the Ks-values for O, C and R were 0.2, 0.9 and 5.1 mM, respectively; for F and N no binding up to 4 mM could be observed. However, in man, only C inhibited the hepatic elimination of diazepam by about 45% while R, O, N and F did not affect the pharmacokinetics of diazepam. Thus, it could be concluded from our studies that one cannot extrapolate in vitro data of the inhibitory potency of H2-receptor antagonists in every case to human in vivo drug metabolism.
mesh_terms: D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D002927:Cimetidine / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D015738:Famotidine; D006635:Histamine H2 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D016567:Nizatidine; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010105:Oxygenases / Q000037:antagonists & inhibitors; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D006635:Histamine H2 Antagonists; D007093:Imidazoles; D004364:Pharmaceutical Preparations; D013844:Thiazoles; D015738:Famotidine; D002927:Cimetidine; D011899:Ranitidine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D016567:Nizatidine; D003975:Diazepam; C027703:oxmetidine