STEREOSELECTIVE IN-VIVO AND IN-VITRO STUDIES ON THE METABOLISM OF DOXEPIN AND N-DESMETHYLDOXEPIN

1. Doxepin is marketed as an irrational mixture of geometric isomers s uch that the more active Z-isomer comprises only 15% of the total doxe pin whereas the less active E-isomer makes up the remaining 85%. 2. Th e ratio of isomers of the doxepin remains approximately Z:E = 15:85 in the plasma of depressed patients whereas plasma levels of the active Z-N-desmethyl metabolite are similar to those of E-N-desmethyldoxepin. 3. After examination of four animal species (dog, rabbit, guinea pig, rat), rat was closest to human in terms of the Z:E ratio of the geome tric isomers of N-desmethyldoxepin excreted in the 0-24-h urine. 4. Ch anges in the urinary Z:E ratio of the metabolite were observed after o ral but not after intravenous or intraperitoneal administration of com mercial doxepin to rat. 5. There was no evidence of Z/E interconversio n after administration of the pure isomers to rat in vivo, or after in cubation of rat or human liver homogenates with pure isomers. 6. In vi tro data suggested that the distortion of the Z:E ratio of N-desmethyl doxepin was a consequence of faster metabolism of the E-isomer in comp arison with Z-N-desmethyldoxepin rather than consequence 'enrichment' of the Z-isomer at the expense of the E-isomer.