Characterization of cimetidine, ranitidine, and related structures' interaction with cytochrome P-450

Cimetidine (I) interacts with the hemin iron of cytochrome P-450 from rat liver microsomes, with its imidazole and cyano coordinating groups. Ranitidine (II) interacts through its nitronic acid oxygen and its amine nitrogen, as shown by optical difference and ESR-spectra. I, N-cyano-N'[2-[[[5-(dimethylamino)-methyl-2-furanyl]methyl] thio]-ethyl]-N"-methyl guanidine (IV), 4(5)-hydroxymethyl-5(4)-methyl imidazole (VII), 4(5)-methyl-5(4)-[(2-aminoethyl)-thiomethyl]-imidazole hydrochloride (IX), 2-[[[(5-dimethylamino)-methyl-2-furanyl]-methyl]-thio]ethene amine dihydrochloride (X) and imidazole (XI) inhibit 7-ethoxycoumarin dealkylation competitively. In I both imidazole and cyano groups contribute to the inhibitory activity, the latter group being more effective according to electron spin resonance. Mixed type inhibition was observed with II, desmethylranitidine (VIII) and N-[[2-(5-methylimidazol-4-yl)methylthio]-ethyl]-N'-methyl-2-nitro-1, 1-ethenediamine (III). These compounds inhibited the reaction to a small extent; ranitidine S-oxide (VI) did not interact at all with microsomes from phenobarbital-pretreated rats. Using microsomes from 3-methylcholanthrene-pretreated rats, the affinities of interaction and the amplitudes of optical difference spectra were higher with VIII than with its parent, compound II.