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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1457983
This article is part of the Research Topic ADME of Drugs to Treat Infectious Diseases View all articles
Quantitative Pulmonary Pharmacokinetics of Tetrandrine for SARS-CoV-2 Repurposing: A Physiologically-Based Pharmacokinetic Modeling Approach
Provisionally accepted- 1 Beijing Institute of Pharmacology & Toxicology, Beijing, China
- 2 Huadong Medical Institute of Biotechniques, Nanjing, China
Tetrandrine (TET), a medication traditionally utilized for silicosis in China, demonstrated anti-SARS-CoV-2 potential in vitro. Recognizing the disparity between in vitro findings and in vivo performance, this study aimed to estimate the free lung concentration of TET using a physiologically-based pharmacokinetic (PBPK) model, thereby linking in vitro activity and in vivo efficacy. Comparative pharmacokinetic studies of TET were performed in rats and dogs to elucidate the pharmacokinetic mechanisms, as well as to discern interspecies variations. These insights facilitated the creation of an animal-specific PBPK model, which was subsequently translated into a human model following thorough validation. Following validation of the pharmacokinetic profile from a literature report on single oral dosing of TET in humans, plasma and lung concentrations were predicted after TET administration at approved dosage levels. Finally, the antiviral efficacy of TET in humans was assessed based on the free drug concentration in the lungs. Both in vivo and in vitro experiments confirmed that the systemic clearance of TET is primarily contributed by hepatic metabolism. Additionally, the lysosomal capture of basic TET was identified as a pivotal factor in its vast distribution volume and heterogeneous tissue distribution, which may modulate the absorption dynamics of TET in the gastrointestinal tract. Notably, the PBPK model-calculated unbound lung concentrations of TET (1.67~1.74 μg/mL) at the recommended clinical dosage surpassed the in vitro threshold for anti-SARS-CoV-2 activity (EC90=1.52 μg/mL). In conclusion, a PBPK model was successfully developed to bridge in vitro activity and in vivo target exposure, which could facilitate TET's repurposing.
Keywords: tetrandrine 1, PBPK 2, pulmonary exposure 3, drug repurpose 4, lysosomal trapping 5
Received: 01 Jul 2024; Accepted: 23 Aug 2024.
Copyright: © 2024 Wang, Dong, Hu, Yang, Wang, Zhang, Zhang and ZHUANG. 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:
Xiaomei ZHUANG, Beijing Institute of Pharmacology & Toxicology, Beijing, China
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