Effects of carbamazepine coadministration on plasma concentrations of the enantiomers of mianserin and of its metabolites

Concentrations of the enantiomers of unconjugated and of total (unconjugate d plus conjugated) mianserin, desmethylmianserin and 8-hydroxymianserin wer e measured in 12 patients before and after the introduction of carbamazepin e. The dose of mianserin was 60 mg/d, carbamazepine was coadministered at 4 00 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 (th e more potent enantiomer) and of unconjugated and total (R)-mianserin. On a verage, plasma concentrations of unconjugated and total (S)-mianserin and o f unconjugated and total (R)-mianserin were 55%, 56%, 66%, and 55%, respect ively of the corresponding values before introduction of carbamazepine. The se results strongly suggest the involvement of CYP3A4, the major CYP enzyme induced by carbamazepine, in the metabolism of both enantiomers of mianser in. A strong decrease in the concentrations of (S)-8-hydroxymianserin was a lso measured (on average, the concentrations were 69% of the corresponding values before carbamazepine introduction). Conversely, plasma concentration s of unconjugated and of total (S)-desmethylmianserin, (R)-desmethylmianser in, 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 wh ose (S)-mianserin concentrations have been stabilized within this therapeut ic window would need to he approximately doubled if carbamazepine, at 400 m g/d, is introduced as a comedication.