In vivo and in vitro stereoselective metabolism of mianserin in mice.
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 agreement with published data on human liver microsomes. The reported stereoselectivities were confirmed in liver homogenates of both male and female mice, whereas the extent of N-demethylation and N-oxidation was dependent on the gender. The in vitro data suggest that hepatic metabolism of mianserin is stereoselective. N-demethylation and N-oxidation demonstrate opposite stereoselectivities, which is also reflected in the urinary metabolic pattern of the enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)
Heinig
R
R
Institut für Pharmazeutische Chemie, Universität Münster, Fed. Rep. of Germany.
Blaschke
G
G
D000818:Animals; D002853:Chromatography, Liquid; D003640:Dealkylation; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008803:Mianserin / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D013237:Stereoisomerism; D013431:Sulfates / Q000378:metabolism
D005965:Glucuronates; D013431:Sulfates; D008803:Mianserin