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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1564174
This article is part of the Research Topic Non-Invasive Methods in Drug Metabolism and Transport: Insights from Biological Samples to Oral Administration View all 3 articles
Acute hypobaric hypoxia attenuates the anti-fatigue effects of pitolisant by downregulating the expression of Organic Cation Transporter 1 and P-glycoprotein
Provisionally accepted- Air Force Medical University, Xi'an, China
Objective: This study investigates the effects of acute hypobaric hypoxia (HH) on the anti-fatigue properties of pitolisant and explores the underlying mechanisms. The aim is to provide a theoretical basis for expanding its clinical indications and optimizing its use in individuals exposed to HH conditions.Methods: The anti-fatigue effects of pitolisant were evaluated using the water maze, novel object recognition, and rotating rod tests. Drug concentrations and dopamine levels were analyzed using High-Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (HPLC-MS/MS). Additionally, gene and protein expression levels of P-glycoprotein (P-gp) and organic cation transporter 1 (OCT1) were assessed to explore the mechanisms by which HH affects pitolisant's pharmacodynamics. Results: A 40 mg/kg dose of pitolisant significantly improved learning, memory, cognitive, and motor functions in sleep-deprived mice under HH conditions (P<0.05). Pharmacokinetic analysis revealed a reduction in pitolisant concentration in the brain under HH conditions. Furthermore, OCT1 protein expression decreased after 1 hour and 1 day of HH exposure (P<0.05), while P-gp expression decreased after 1 hour (P<0.05).Conclusion: HH possibly reduced pitolisant's brain concentration and efficacy by altering the expression of OCT1 and P-gp transporters. A 40 mg/kg dose was necessary for an effective anti-fatigue response. Pitolisant shows potential for supporting circadian rhythm regulation in shift workers and individuals suffering from jet lag. When used under HH conditions, adjusting the dose and frequency may be necessary due to altered pharmacokinetics.
Keywords: Pitolisant, hypobaric hypoxia, Pharmacodynamics, drug transporters, LC-MS/MS
Received: 21 Jan 2025; Accepted: 02 Apr 2025.
Copyright: © 2025 Zhao, Li, Liu, Chang, Shen, Xue and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Junhui Xue, Air Force Medical University, Xi'an, China
Fengzhou Liu, Air Force Medical University, Xi'an, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.