Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism

Clin Pharmacol Ther. 1994 Aug;56(2):176-83. doi: 10.1038/clpt.1994.121.

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 (rs = 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 Enzyme System / metabolism
  • Debrisoquin / chemistry
  • Debrisoquin / metabolism*
  • European Continental Ancestry Group
  • Female
  • Humans
  • Hydroxylation
  • Male
  • Mephenytoin / chemistry
  • Mephenytoin / metabolism*
  • Mianserin / administration & dosage
  • Mianserin / analogs & derivatives
  • Mianserin / blood
  • Mianserin / metabolism
  • Mianserin / pharmacokinetics*
  • Middle Aged
  • Mixed Function Oxygenases / metabolism
  • Polymorphism, Genetic*
  • Stereoisomerism
  • Sweden

Substances

  • Mianserin
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP2D6
  • desmethylmianserin
  • Mephenytoin
  • Debrisoquin