Geometric isomerization of doxepin during its N-demethylation in humans

The N-demethylation of the individual Z-(cis) and E-(trans) isomers of the tricyclic antidepressant doxepin was studied by examining the 0-8 hr serum concentration-time and the 0-72 hr urinary excretion profiles of parent drug and metabolite in eight healthy males who had received a single oral dose consisting of 25 mg each of Z-[2H0]- and E-[2H4]-labeled drug as the hydrochloride salt. Interconversion of doxepin's isomers was not observed but stereoselective excretion was present. Significant amounts of Z-N-desmethyldoxepin were formed and excreted after dosing with E-doxepin, the urinary Z/E ratio ranging from 0.08 to 3.06. A small amount of nondeuterated E-N-desmethyldoxepin was formed from Z-doxepin in most, but not all, subjects. These findings indicate that isomerization occurs during the N-demethylation of doxepin, possibly involving the formation of an intermediate in which the exocyclic double bond is hydrated and then subseqently dehydrated. This novel biotransformation process accounts for the observation that the Z/E plasma concentration ratio of N-desmethyldoxepin is often greater than that of the administered doxepin in patients receiving the drug therapeutically.