Doxepin, a tricyclic antidepressant, is a potent histamine H1 antagonist [1]. The histamine receptors belong to a family of G protein–coupled receptors activated by their primary endogenous ligand histamine. The H1 receptor has been expressed in smooth muscles, vascular endothelial cells, heart, and the central nervous system [2].
In vitro: Doxepin was a moderately potent competitive inhibitor of serotonin uptake in human blood platelets in vitro, with an inhibitory constant Ki of ～0.2 μM. Doxepin (100 μM) rapidly increased the efflux of serotonin from platelets [1].
In vivo: In rats and dog, oral administration of doxepin was well absorbed and quickly appeared in the blood. Numerous metabolites of doxepin were observed in liver and in urine, only doxepin and demethyl doxepin were found in the rat brain[3]..
Clinical trials: Doxepin has been marketed under many brand names worldwide. The oral topical formulations of doxepin are FDA-approved for the treatment of patients with major depressive disorder, primary insomnia, chronic urticaria, and anxiety [4,5,6].
References:
[1] Lingjrde O. Effect of doxepin on uptake and efflux of serotonin in human blood patelets in vitro[J]. Psychopharmacology, 1976, 47(2): 183-186.
[2] Hill S J, Ganellin C R, Timmerman H, et al. International Union of Pharmacology. XIII. Classification of histamine receptors[J]. Pharmacological reviews, 1997, 49(3): 253-278.
[3] Hobbs D C. Distribution and metabolism of doxepin[J]. Biochemical pharmacology, 1969, 18(8): 1941-1954.
[4] Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study[J]. Journal of Clinical Psychiatry, 2001, 62(6): 453-463.
[5] Feighner J P, Cohn J B. Double-blind comparative trials of fluoxetine and doxepin in geriatric patients with major depressive disorder[J]. The Journal of clinical psychiatry, 1985, 46(3 Pt 2): 20-25.
[6] Goldsobel A B, Rohr A S, Siegel S C, et al. Efficacy of doxepin in the treatment of chronic idiopathic urticaria[J]. Journal of allergy and clinical immunology, 1986, 78(5): 867-873.