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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All authors acknowledge BVDU and Cleanchem Life Sciences for their support and encouragement.
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The funding for the experimental work was provided by Cleanchem Lifesciences LPP, Navi, Mumbai.
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The animal experiments were carried out in accordance with the protocol (1120/IAEC/2022-2023; dated 12/08/2022) approved by the Institutional Animal Ethics Committee (IAEC), AIIMS, New Delhi and as per the guidelines laid down by the Committee for Control and Supervision of Experimental Animals (CCSEA), New Delhi.
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R.R. wrote the manuscript with support from S.M., L.A. and U.A. D.K. contributed for the analysis and interpretation of data for this manuscript. B.G. and K.P. helped R.R. to supervise the project.
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Moharir, S., Akotkar, L., Aswar, U. et al. Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models. Eur J Drug Metab Pharmacokinet 49, 181–190 (2024). https://doi.org/10.1007/s13318-023-00870-4
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DOI: https://doi.org/10.1007/s13318-023-00870-4