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03-01-2024 | Doxepin | Original Research Article

Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models

Authors: Shreyash Moharir, Likhit Akotkar, Urmila Aswar, Dileep Kumar, Bapu Gawade, Kavita Pal, Rajesh Rane

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 2/2024

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Abstract

Background and Objectives

Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selective deuteration of TCAs on their pharmacokinetic and pharmacodynamic profile by comparison with their nondeuterated counterparts.

Methods

In the current study, the pharmacokinetic profile and antidepressant behavior of deuterated TCAs were evaluated using the forced swim test (FST) and tail suspension test (TST), using male Wistar rats and male Swiss albino mice, respectively; additionally, a synaptosomal reuptake study was carried out.

Results

Compared with the nondeuterated parent drugs, deuterated forms showed improved efficacy in the behavior paradigm, indicating improved pharmacological activity. The pharmacokinetic parameters indicated increased maximum concentration in the plasma (Cmax), elimination half-life (t1/2), and area under the concentration-time curve (AUC)  in deuterated compounds. This can have a positive clinical impact on antidepressant treatment. Synaptosomal reuptake studies indicated marked inhibition of the reuptake mechanism of serotonin (5-HT) and norepinephrine.

Conclusions

Deuterated TCAs can prove to be potentially better molecules in the treatment of neuropsychiatric disorders as compared with nondeuterated compounds. In addition, we have demonstrated a concept that metabolically active, site-selective deuteration can be beneficial for improving the pharmacokinetic and pharmacodynamic profiles of TCAs. A further toxicological study of these compounds is needed to validate their future clinical use.
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Metadata
Title
Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models
Authors
Shreyash Moharir
Likhit Akotkar
Urmila Aswar
Dileep Kumar
Bapu Gawade
Kavita Pal
Rajesh Rane
Publication date
03-01-2024
Publisher
Springer International Publishing
Published in
European Journal of Drug Metabolism and Pharmacokinetics / Issue 2/2024
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI
https://doi.org/10.1007/s13318-023-00870-4