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Disassociating drug active ingredients from inactive: ketamine-like synaptic effects of a ketamine excipient

Neuropsychopharmacology volume 49, pages 301–302 (2024)Cite this article

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Excipients are formulated in combination with an active pharmaceutical ingredient in many drug products. While excipients are expected to be inert, emerging evidence suggests that many are pharmacologically active and may partly underlie or modify the functional effects attributed to the active pharmaceutical ingredient [1]. Enhanced interest in the biological activity of excipients has led to studies assessing the contribution of excipients to adverse reactions induced by drug products. For instance, clinically relevant concentrations of Cremophor EL, an excipient used as a formulation vehicle for paclitaxel in the drug product Taxol®, were shown to promote the production of triglycerides in vitro. Notably, breast cancer patients treated with Taxol® exhibited enhanced levels of blood triglycerides and dyslipidemia compared to patients treated with the Cremophor EL-free paclitaxel-based chemotherapy [2].

Biologically active excipients may also confound the interpretation of the pharmacological effects attributed to the drug substance. For example, the antimicrobial and antibacterial excipient benzethonium chloride (BZT) is used as a preservative in human and veterinary ketamine drug products. The typical BZT concentration in these products is 0.1% BZT, though some products contain up to 0.2%. Thus, a ketamine drug product solution when diluted to 10 µM ketamine may include up to 12 nM BZT. Some reports indicate that BZT is pharmacologically active [1], with numerous functional effects being observed in vitro at low nM concentrations. These effects include inhibition of currents mediated by activation of nicotinic and muscarinic receptors [3, 4] as well as the human ether-a-go-go-related gene channel [5] ectopically expressed in Xenopus oocytes and mammalian cells. Additionally, the combination of ketamine and BZT exhibit synergistic inhibitory effects on muscarinic receptor function [4]. These reports suggest that the presence of BZT in ketamine formulations may independently impact endpoints measured in experiments, and that some pharmacological effects previously attributed to the action of ketamine may be influenced by BZT.

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References

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Funding

Funding

This work was supported by NIH/NIMH R01MH107615 and U.S. Department of Veterans Affairs Merit Awards 1I01BX004062 and 1I01BX006018 to TDG. The binding and functional profile of BZT were performed by the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP; University of North Carolina, Chapel Hill, NC; Contract # HHSN-271-2018-00023-C). The NIMH PDSP is directed by Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Kyle A. Brown & Todd D. Gould

  2. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Todd D. Gould

  3. Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Todd D. Gould

  4. Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA

    Todd D. Gould

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  1. Kyle A. Brown
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Contributions

KAB and TDG contributed to the conception of the work; KAB wrote the manuscript and TDG critically revised the work.

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Correspondence to Todd D. Gould.

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Competing interests

TDG has received research funding from Allergan Pharmaceuticals during the preceding three years. TDG is listed as an inventor in patents and patent applications related to the pharmacology and use of a ketamine metabolite, (2 R,6 R)-hydroxynorketamine, in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. TDG has assigned his patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland, Baltimore. KAB declares no competing interests.

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Brown, K.A., Gould, T.D. Disassociating drug active ingredients from inactive: ketamine-like synaptic effects of a ketamine excipient. Neuropsychopharmacol. 49, 301–302 (2024). https://doi.org/10.1038/s41386-023-01675-4

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