In vitro studies on the metabolic fate of mifentidine, a novel histamine H2-receptor antagonist

The in vitro metabolism of mifentidine and several of its metabolites was studied using hepatic microsomes from seven animal species. The effects of potential enzyme inducers, inhibitors and activators were also studied. Mifentidine metabolites identified and characterised were: 4-imidazolylphenylamine (amine), 4-imidazolylphenyl-formamide (formamide), the urea derivative of mifentidine (urea) and the imidazole-hydroxylated derivative of the amine (i-OH-amine), along with three unidentified metabolites, M1, M2 and M3. Evidence for the presence of the amine, formamide, urea and i-OH-amine was obtained by comparison with authentic reference compounds: (i) HPLC retention times; (ii) UV spectra; and (iii) MS spectra of metabolites. The postulated intermediates are: carbinolimine (for formamide, amine, i-OH-amine and urea formation); formamide (for amine and i-OH-amine formation); amine (for i-OH-amine formation), and nitrone (for urea formation). One ‘metabonate’ of mifentidine was also identified, namely the nitro analogue of the amine. A possible prerequisite for the formation of this nitro is the corresponding hydroxylamine or nitroso compound. Cytochromes P450I and P450II were shown to be involved in the in vitro microsomal biotransformation of mifentidine, but the involvement of the flavin monooxygenase system was not proven.