title: Effects of carbamazepine coadministration on plasma concentrations of the enantiomers of mianserin and of its metabolites.
abstract: Concentrations of the enantiomers of unconjugated and of total (unconjugated plus conjugated) mianserin, desmethylmianserin and 8-hydroxymianserin were measured in 12 patients before and after the introduction of carbamazepine. The dose of mianserin was 60 mg/d, carbamazepine was coadministered at 400 mg/d for 4 weeks, and blood samples were taken at weekly intervals after the introduction of carbamazepine. Each week, carbamazepine significantly decreased plasma concentrations of unconjugated and total (S)-mianserin (the more potent enantiomer) and of unconjugated and total (R)-mianserin. On average, plasma concentrations of unconjugated and total (S)-mianserin and of unconjugated and total (R)-mianserin were 55%, 56%, 66%, and 55%, respectively, of the corresponding values before introduction of carbamazepine. These results strongly suggest the involvement of CYP3A4, the major CYP enzyme induced by carbamazepine, in the metabolism of both enantiomers of mianserin. A strong decrease in the concentrations of (S)-8-hydroxymianserin was also measured (on average, the concentrations were 69% of the corresponding values before carbamazepine introduction). Conversely, plasma concentrations of unconjugated and of total (S)-desmethylmianserin, (R)-desmethylmianserin, and (R)-8-hydroxymianserin were only slightly modified by carbamazepine. From a clinical point of view, as a therapeutic window for (S)-mianserin has been recently suggested, the dose of racemic mianserin for a patient whose (S)-mianserin concentrations have been stabilized within this therapeutic window would need to be approximately doubled if carbamazepine, at 400 mg/d, is introduced as a comedication.
authors.affiliation: Unit of Biochemistry and Clinical Psychopharmacology, Hôpital de Cery, Prilly-Lausanne, Switzerland.
authors.forename: C B
authors.initials: CB
authors.lastname: Eap
authors.forename: N
authors.initials: N
authors.lastname: Yasui
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
authors.forename: P
authors.initials: P
authors.lastname: Baumann
authors.forename: K
authors.initials: K
authors.lastname: Powell
authors.forename: K
authors.initials: K
authors.lastname: Otani
mesh_terms: D000328:Adult; D000368:Aged; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000493:pharmacokinetics*; D018692:Antimanic Agents / Q000097:blood / Q000494:pharmacology*; D002220:Carbamazepine / Q000097:blood / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008803:Mianserin / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D018687:Antidepressive Agents, Second-Generation; D018692:Antimanic Agents; D008803:Mianserin; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human