Stereoselective pharmacokinetics of doxepin isomers

Commercial preparations of the tricyclic anti-depressant doxepin contain 15% of the more active cis-doxepin and 85% of the trans-isomer. The single dose pharmacokinetics of doxepin and its major metabolite N-desmethyldoxepin were examined in 30 healthy young men. Results for total doxepin showed wide intersubject variation in all pharmacokinetic parameters except tmax and Cmax. Plasma levels of cis-doxepin were extremely low and it was only possible to estimate the stereoselective pharmacokinetics of the parent drug in 3 subjects. The data from those particular subjects resulted in an average ratio of cis- to trans-doxepin isomers in plasma of 15:85. In contrast, the mean plasma levels of cis-N-desmethyldoxepin in 28 subjects exceeded those of the trans-isomer at every time point after 10 h, such that the areas under the plasma concentration versus time curves (AUC) of cis-N-desmethyldoxepin were significantly higher than those of the corresponding trans-isomer. This phenomenon may play an important role in the therapeutic action of doxepin since it has been suggested that cis-N-desmethyldoxepin is pharmacologically active. In 2 subjects, however, the AUC0-inf of trans-N-desmethyldoxepin were respectively 4 and 8 fold higher than those of the cis-isomer.