Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism

Abstract

The pharmacokinetics of mianserin and its main metabolite desmethylmianserin were studied in poor and extensive metabolizers of debrisoquin and of S-mephenytoin after a single oral dose of racemic mianserin. The debrisoquin metabolic ratio (MR) correlated significantly with area under the serum concentration-time curves (AUC) for (±)-mianserin and (±)-desmethylmianserin. Enantioselective high-performance liquid chromatographic analysis of mianserin showed that debrisoquin MR was related to AUC(0-12) for S(+)-mianserin (r(s) = 0.87; p = 0.001; n = 15) but not for R(-)-mianserin. The ratio between the AUC(0-12) for S(+)-mianserin and that for R(-)-mianserin was higher in poor metabolizers than in extensive metabolizers. Two extremely rapid extensive metabolizer subjects had the lowest mianserin S/R ratios. No differences in the pharmacokinetics of mianserin or desmethylmianserin were found between extensive metabolizers and poor metabolizers of S-mephenytoin. The study shows that the elimination of both mianserin and its main metabolite desmethylmianserin is dependent on CYP2D6 activity. Furthermore, the CYP2D6-dependent elimination of mianserin shows marked enantioselectivity for the more active S(+)-enantiomer of mianserin.