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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1510903
This article is part of the Research Topic New Drugs and Future Challenges in Drug Metabolism and Transport View all 14 articles

The in vivo metabolic pathway of Deg-AZM and in vitro investigations into the contribution of drug metabolizing enzymes and drug transporters in the drug interactions of Deg-AZM, a clinical-stage new transgelin agonist

Provisionally accepted
Xiaoting Gu Xiaoting Gu 1*Xiaohe Li Xiaohe Li 1Weixue Tian Weixue Tian 2*Chaoyue Zheng Chaoyue Zheng 1*Yutian Cai Yutian Cai 1*Xiang Xu Xiang Xu 1*Conglu Zhao Conglu Zhao 1*Hongting Liu Hongting Liu 1*Yao Sun Yao Sun 1*Zhilin Luo Zhilin Luo 1*Shuwen Zhu Shuwen Zhu 1*Honggang Zhou Honggang Zhou 1*Xiaoyu Ai Xiaoyu Ai 1*Cheng Yang Cheng Yang 1*
  • 1 College of Pharmacy, Nankai University, Tianjin, China
  • 2 The National Institutes of Pharmaceutical R&D Co., Ltd, Beijing, China

The final, formatted version of the article will be published soon.

    Deglycosylated azithromycin (Deg-AZM), a new transgelin agonist with positive therapeutic effects on slow transit constipation, has been approved for clinical trials in 2024. This work investigated the drug metabolism and transport of Deg-AZM to provide research data for further development of Deg-AZM. Metabolic pathway study found 44 metabolites in rat urine, feces, bile, and plasma after administration of Deg-AZM. The main metabolic pathways of Deg-AZM include demethylation, monohydroxylation, dihydroxylation, dehydroxidation, hydroreduction, hydrolysis, methylation, glucuronidation and the combination of different metabolic pathways.The study on Caco-2 cell permeability indicate that Deg-AZM was a low permeability drug in the intestine and a potential substrate of the efflux transporter P-glycoprotein (P-gp). Phenotyping studies indicated cytochrome P450 (CYP) 3A4 was the major CYP isoform responsible for Deg-AZM metabolism. Deg-AZM showed moderate inhibition with half maximal inhibitory concentration (IC50) of 11.9 and 9.26 μM for CYP2B6 and CYP2D6 respectively. Data in three batches of human primary hepatocytes disclosed induction potential of Deg-AZM on CYP2B6 and CYP3A4. The in vitro results with CYPs and transporter indicated that CYP3A and P-gp inhibitors and inducers may impact systemic exposure of Deg-AZM and caused drug-drug interactions (DDIs). Dose adjustments may be warranted depending on the potency of the corresponding modulators.

    Keywords: 38 Tongyan Road, Jinnan District, Tianjin, P.R.China 300350 Deglycosylated azithromycin, Drug-drug interactions, CYP enzymes, Caco-2 cell, P-gp, Metabolic pathways AP, Apical, BL, Basolateral, Caco-2, the human colon adenocarcinoma cell line, CYP, cytochrome P450, DDIs, drug-drug interactions, Deg-AZM, Deglycosylated azithromycin, ER, efflux ratio, HBSS, Hank's Balanced Salt Solution

    Received: 14 Oct 2024; Accepted: 17 Dec 2024.

    Copyright: © 2024 Gu, Li, Tian, Zheng, Cai, Xu, Zhao, Liu, Sun, Luo, Zhu, Zhou, Ai and Yang. 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:
    Xiaoting Gu, College of Pharmacy, Nankai University, Tianjin, China
    Weixue Tian, The National Institutes of Pharmaceutical R&D Co., Ltd, Beijing, China
    Chaoyue Zheng, College of Pharmacy, Nankai University, Tianjin, China
    Yutian Cai, College of Pharmacy, Nankai University, Tianjin, China
    Xiang Xu, College of Pharmacy, Nankai University, Tianjin, China
    Conglu Zhao, College of Pharmacy, Nankai University, Tianjin, China
    Hongting Liu, College of Pharmacy, Nankai University, Tianjin, China
    Yao Sun, College of Pharmacy, Nankai University, Tianjin, China
    Zhilin Luo, College of Pharmacy, Nankai University, Tianjin, China
    Shuwen Zhu, College of Pharmacy, Nankai University, Tianjin, China
    Honggang Zhou, College of Pharmacy, Nankai University, Tianjin, China
    Xiaoyu Ai, College of Pharmacy, Nankai University, Tianjin, China
    Cheng Yang, College of Pharmacy, Nankai University, Tianjin, China

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