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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1443794

In Vitro Mechanistic Study on Mycophenolate Mofetil Drug Interactions: Effect of Prednisone, Cyclosporine, and Others

Provisionally accepted
Junjun Mao Junjun Mao 1Feifei Yu Feifei Yu 2Weiwei Qin Weiwei Qin 1Guixian She Guixian She 3Yi Rong Yi Rong 3Zhuohan Hu Zhuohan Hu 3Ming-kang Zhong Ming-kang Zhong 1*
  • 1 Huashan Hospital, Fudan University, Shanghai, China
  • 2 Independent researcher, Shanghai, China
  • 3 Research Institute for Liver Diseases (RILD), Shanghai, China

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

    Objective The metabolism- and transporter- based drug-drug interactions (DDIs) between mycophenolate mofetil (MMF) and co-administered medications may be key factors for the high individual variability in MMF exposure. This study systematically assessed the influence of co-medications on the mycophenolic acid (MPA) pharmacokinetic (PK) process in vitro, particularly to provide mechanistic evidence of the metabolic interaction among steroids, cyclosporine (CsA), and MMF. Methods Based on a previous study, we hypothesized that there are three main DDI pathways affecting MMF PK in vivo. A human hepatocyte induction study, transporter substrate/inhibition study using human embryonic kidney 293 cells, and multidrug resistance-associated protein 2 (MRP2) substrate/inhibition study using vesicle membrane were conducted to assess the mechanistic evidence of the metabolic interaction in triple therapies. The potential DDI risks associated with seven medications commonly co-administered with MMF in clinical practice were further evaluated. Results The in vitro results suggested that prednisolone, the active metabolite of prednisone, induces the enzymatic activity of uridine 5'-diphospho-glucuronosyltransferase (UGT), particularly the UGT1A9 and UGT2B7 isoforms, resulting in increased metabolism of MPA to MPA glucuronide (MPAG). This induction potential was not observed in CsA-treated human hepatocytes. CsA inhibits organic anion-transporting polypeptide (OATP) 1B1- and OATP1B3-mediated MPAG. Prednisolone and CsA showed no inhibitory effect on MRP2-mediated MPAG efflux. Salvia miltiorrhiza significantly inhibited OATP and OAT 3 activities, suggesting that it affects the hepatic uptake and renal excretion of MPAG, causing increased MPAG exposure in vivo. Conclusions These identified factors may contribute to the high inter-individual variability in MMF exposure and facilitate further development of mechanistic MMF PK models and individualized therapies.

    Keywords: Mycophenolate mofetil, Cyclosporine, Prednisolone, Salvia miltiorrhiza, Drug-Drug Interaction

    Received: 04 Jun 2024; Accepted: 12 Aug 2024.

    Copyright: © 2024 Mao, Yu, Qin, She, Rong, Hu and Zhong. 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: Ming-kang Zhong, Huashan Hospital, Fudan University, Shanghai, China

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