Doxepin is a
tricyclic antidepressant (TCA). and its effectiveness as an
analgesic (including in the treatment of
neuropathic pain, and as a
local anesthetic). • Extremely strong:
Histamine H1 receptor • Strong:
α1-adrenergic receptor,
5-HT2A and
muscarinic acetylcholine receptors • Moderate:
5-HT2C and
5-HT1A receptors • Weak:
α2-adrenergic and
D2 receptors Based on its values for monoamine reuptake inhibition, doxepin is relatively selective for the inhibition of
norepinephrine reuptake, with a much weaker effect on the
serotonin transporter. Although there is a significant effect that takes place at one of the specific serotonergic binding sites, the
5-HT2A serotonin receptor subtype. There is negligible influence on dopamine reuptake. In general, the demethylated variants of
tertiary amine TCAs like
Nortriptyline,
Desipramine and
nordoxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities. Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day. At low doses, below 25 mg, doxepin is a pure antihistamine and has more of a
sedative effect. In fact, doxepin has been said to be the most or one of the most potent H1 receptor antagonists available, with one study finding an
in vitro Ki of 0.17 nM. and other sedating antihistamines, for instance the
over-the-counter diphenhydramine (Ki = 16 nM) and
doxylamine (Ki = 42 nM), show far lower affinities for this receptor in comparison. In accordance, although it is often described as a "
dirty drug" due to its highly promiscuous binding profile, However, doxepin is a unique and notable exception; it has been well-studied in the treatment of insomnia and shows consistent benefits with excellent
tolerability and
safety. The
effect sizes of very low-dose doxepin in the treatment of insomnia range from small to medium. Although doxepin is selective for the H1 receptor at doses lower than 25 mg, blockade of serotonin and adrenergic receptors may also be involved in the hypnotic effects of doxepin at higher doses. While it significantly altered metabolic ratios for
sparteine and its
metabolites, doxepin did not convert any of the patients to a different metabolizer phenotype (e.g., extensive to intermediate or poor). Following a single very low dose of 6 mg, peak plasma levels of doxepin are 0.854 ng/mL (3.06 nmol/L) at 3 hours without food and 0.951 ng/mL (3.40 nmol/L) at 6 hours with food.
Area-under-curve levels of the drug are increased significantly when it is taken with food.
Metabolism Doxepin is extensively
metabolized by the
liver via
oxidation and
N-
demethylation. The major active metabolite of doxepin,
nordoxepin, is formed mainly by CYP2C19 (>50% contribution), while CYP1A2 and CYP2C9 are involved to a lesser extent, and CYP2D6 and CYP3A4 are not involved. Both doxepin and nordoxepin are
hydroxylated mainly by CYP2D6, and both doxepin and nordoxepin are also
transformed into
glucuronide conjugates. Up to 10% of
Caucasian individuals show substantially reduced metabolism of doxepin that can result in up to 8-fold elevated plasma concentrations of the drug compared to normal. Nordoxepin is a
mixture of
(E) and (Z) stereoisomers similarly to doxepin. 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.
Elimination Doxepin is
excreted primarily in the urine and predominantly in the form of
glucuronide conjugates, with less than 3% of a dose excreted unchanged as doxepin or nordoxepin.
Pharmacogenetics Since doxepin is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of doxepin may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. Individuals can be categorized into different types of
cytochrome P450 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most people are extensive metabolizers, and have "normal" metabolism of doxepin. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers break down doxepin much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. A study assessed the metabolism of a single 75 mg oral dose of doxepin in healthy volunteers with
genetic polymorphisms in CYP2D6, CYP2C9, and CYP2C19 enzymes. In CYP2D6
extensive,
intermediate, and
poor metabolizers, the mean
clearance rates of (
E)-doxepin were 406, 247, and 127 L/hour, respectively (~3-fold difference between extensive and poor). In addition, the bioavailability of (
E)-doxepin was about 2-fold lower in extensive relative to poor CYP2D6 metabolizers, indicating a significant role of CYP2D6 in the
first-pass metabolism of (
E)-doxepin. The clearance of (
E)-doxepin in CYP2C9
slow metabolizers was also significantly reduced at 238 L/hour. CYP2C19 was involved in the metabolism of (
Z)-doxepin, with clearance rates of 191 L/hour in CYP2C19 extensive metabolizers and 73 L/hour in poor metabolizers (~2.5-fold difference).
Area-under-the-curve (0–48 hour) levels of nordoxepin were dependent on the
genotype of CYP2D6 with median values of 1.28, 1.35, and 5.28 nM•L/hour in CYP2D6 extensive, intermediate, and poor metabolizers, respectively (~4-fold difference between extensive and poor). Taken together, doxepin metabolism appears to be highly
stereoselective, and CYP2D6 genotype has a major influence on the pharmacokinetics of (
E)-doxepin. Moreover, CYP2D6 poor metabolizers, as well as patients taking potent CYP2D6 inhibitors (which can potentially convert a CYP2D6 extensive metabolizer into a poor metabolizer), may be at an increased risk for adverse effects of doxepin due to their slower clearance of the drug. Another study assessed doxepin and nordoxepin metabolism in CYP2D6
ultra-rapid, extensive, and poor metabolizers following a single 75 mg oral dose. They found up to more than 10-fold variation in total exposure to doxepin and nordoxepin between the different groups. The researchers suggested that in order to achieve equivalent exposure, based on an average dose of 100%, the dosage of doxepin might be adjusted to 250% in ultra-rapid metabolizers, 150% in extensive metabolizers, 50% in intermediate metabolizers, and 30% in poor metabolizers. ==Chemistry==