Doxepin inhibits CYP2D6 activity in vivo.

Objective: Doxepin is a tricyclic antidepressant formulated as a mixture of E-(trans) and Z-(cis) stereoisomers. Cytochrome P450 2D6 (CYP2D6) catalyzes the hydroxylation of E-doxepin and E-N-desmethyldoxepin stereospecically. There is evidence that tricyclic antidepressants might inhibit CYP2D6 activity but there is no data about the influence of doxepin on CYP2D6.

Materials and methods: Eleven patients diagnosed with depression according to ICD-10 criteria were included in the study. After wash-out period, before doxepin treatment, sparteine metabolic ratio (MR1) was assessed. After 2-weeks of doxepin treatment, MR2 was estimated. Sparteine and its metabolites were determined in urine by gas chromatographic method of Eichelbaum et al.

Results: Based on MR1 values, 10 patients were classified as EM (extensive metabolizers) and 1 patient as PM (poor metabolizer). During the study, after doxepin treatment, none of patients has changed phenotype status. However, MR2 values were statistically significantly higher than MR1.

Conclusion: These results show the inhibitory effect of doxepin on CYP2D6 activity and may be of clinical value, especially in polymedicated patients treated with other CYP2D6 substrates or inhibitors.