Nordoxepin, also known as , is the major N-desmethyldoxepin active metabolite of the tricyclic antidepressant (TCA) doxepin (Sinequan). It has been found to play a significant role in the  antidepressant effects of doxepin.
Nordoxepin is a
mixture of ( E) and ( Z) stereoisomers. Whereas  pharmaceutical doxepin is supplied in an approximate 85:15 ratio mixture of ( E)- and ( Z)-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the ( E)- and ( Z)-stereoisomers of nordoxepin, due to stereoselective metabolism of doxepin by cytochrome P450 enzymes, are approximately 1:1.
pharmacologically active similarly to doxepin, but relative to doxepin, is much more  potent and selective as a norepinephrine reuptake inhibitor.   In general, the demethylated variants of  tertiary amine TCAs like doxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.  
Nordoxepin is formed from doxepin mainly by
CYP2C19 (>50% contribution), while CYP1A2 and CYP2C9 are involved to a lesser extent, and CYP2D6 and CYP3A4 are not involved.  Hydroxylation of doxepin and nordoxepin is mediated mainly by CYP2D6. Total exposures to both doxepin and nordoxepin differ by almost 10-fold in CYP2D6  ultra-rapid versus poor metabolizers. Both doxepin and nordoxepin are also  transformed into glucuronide conjugates. The  elimination half-life of nordoxepin is approximately 31 hours, which is almost twice that of doxepin (mean 17 hours).
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