Differential inhibition of human liver phenacetin O-deethylation by histamine and four histamine H2-receptor antagonists.

1. The effects of histamine and four histamine H-2 receptor antagonists on phenacetin O-deethylation by microsomal preparations of four human livers was quantified by a radiometric-thin layer chromatographic method. 2. Histamine and three of these drugs, namely cimetidine, ranitidine and famotidine, were weak inhibitors of this cytochrome P-450-catalysed O-deethylation, but mifentidine was a potent competitive inhibitor with a Ki in the range 40-70 microM. 3. Cimetidine, histamine and mifentidine are all 4(5)-substituted imidazole derivatives, and the contrast between the very weak inhibitory effects of cimetidine and histamine, and the more potent effect of mifentidine, suggests that the imidazole moiety may play little role in the inhibition of phenacetin O-deethylase by mifentidine. 4. The demonstration that cimetidine, ranitidine and histamine were all poor inhibitors of phenacetin oxidation further suggests the possible lack of identity between the human liver cytochrome P-450 isoenzymes responsible for catalyzing the oxidation of metoprolol and phenacetin. This follows from recognizing that metoprolol oxidation is known, from both in vivo and in vitro studies, to be strongly inhibited by both of these H-2 receptor antagonists and from in vitro studies also to be inhibited by histamine.