PMID: 8447847Jan 1, 1993Paper

In vivo and in vitro stereoselective metabolism of mianserin in mice

Arzneimittel-Forschung
R Heinig, G Blaschke

Abstract

The preparative separation of mianserin (CAS 24219-97-4) enantiomers, both of unlabelled compound in g-amounts and radiolabelled compound as used for metabolism studies in microgram-amounts, is facilitated by means of LC on microcrystalline cellulose triacetate (CTA). HPLC on CTA is used for confirmation of the enantiomeric purity. After administration of 14C-labelled enantiomers to mice AUC and Cmax of the S-enantiomer were increased by 48% and 128%, resp. With regard to urinary metabolites from rac mianserin 97.9% of the radioactivity was excreted in conjugated form. Glucuronidation (82.1%) was preferred to sulphation (15.8%). The excretion of N-demethylated metabolites was increased after dosage of R-mianserin, demonstrated by an R:S ratio of 5.2 (8-hydroxy-demethylmianserin glucuronide), while the S-enantiomer was mainly metabolized to 8-hydroxymianserin glucuronide (S:R = 3.2). The 8-hydroxymianserin N(2) oxide was selective for the S-isomer. In mouse liver homogenate with NADPH as cosubstrate the overall extent of metabolism was greater for R-mianserin (87.1% R vs. 44.1% S). The R-enantiomer prefers N-demethylation (R:S = 3.4-4.0) while more N-oxidized metabolites are formed from S-mianserin (S:R = 2.5), which is in agree...Continue Reading

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