A stereochemical investigation of the cytotoxicity of mianserin metabolites in vitro

Abstract

1. The metabolism of the enantiomers of mianserin to stable, chemically reactive and cytotoxic metabolites by human liver microsomes has been investigated in vitro. 2. Both enantiomers were metabolised to three major oxidation products: 8-hydroxymianserin, desmethylmianserin and mianserin 2-oxide. Hydroxylation occurred more readily with the S-enantiomer, whereas desmethylmianserin was always the major metabolite of the R-enantiomer. 3. The generation of chemically reactive metabolites exhibited a marginal degree of stereoselectivity, as assessed by irreversible binding of drug to microsomal protein (S greater than or equal to R; P less than or equal to 0.05). 4. The formation of metabolites which were cytotoxic towards human mononuclear leucocytes was greater (P less than or equal to 0.001] for R(-)-mianserin than for S(+)-mianserin and showed a significant correlation with N-demethylation (r = 0.84, P less than or equal to 0.01).