Quantitative Characterization of Drug Metabolism and Transport Alterations in Obesity with Metabolic Fatty Liver Disease: A Physiologically Based Pharmacokinetic Modelling Approach: Drug Metabolism and Transport in MAFLD: A PBPK Modelling Approach

Yuewu Xie; Xiaoqin Bai; Chaozhuang Shen; Chaoran Xu; Chi Cui; Yujie Yang

doi:10.1016/j.xphs.2025.103906

Quantitative Characterization of Drug Metabolism and Transport Alterations in Obesity with Metabolic Fatty Liver Disease: A Physiologically Based Pharmacokinetic Modelling Approach: Drug Metabolism and Transport in MAFLD: A PBPK Modelling Approach

J Pharm Sci. 2025 Jul 11:103906. doi: 10.1016/j.xphs.2025.103906. Online ahead of print.

Authors

Yuewu Xie¹, Xiaoqin Bai², Chaozhuang Shen³, Chaoran Xu⁴, Chi Cui⁵, Yujie Yang⁶

Affiliations

¹ School of Pharmacy, Wannan Medical College, 22 West Wenchang Road, Wuhu, 241002, PR China.
² Medical Research Center, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, China.
³ Department of Clinical Pharmacy and Pharmacy Administration, West China school of Pharmacy, Sichuan University, Chengdu 610064, China.
⁴ Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan. China.
⁵ Department of General Surgery, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, China.
⁶ Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan. China. Electronic address: scuyangyujie@163.com.

PMID: 40653046
DOI: 10.1016/j.xphs.2025.103906

Abstract

Background: Metabolic fatty liver disease (MAFLD), a condition characterized by impaired hepatic and intestinal metabolic function, predominantly affects the in vivo drug process of obese individuals. Despite its clinical significance, the impact of MAFLD on drug metabolism enzymes and transporters throughout disease progression remains poorly understood. This study aimed to quantitatively characterize alterations during MAFLD progression and develop a comprehensive physiologically based pharmacokinetic (PBPK) model incorporating both intra- and extrahepatic drug transport and metabolic changes to predict drug disposition.

Methods: We established high fat diet (HFD)- fed mice across five progressive stages (8, 16, 24, 32, and 40 weeks). Hepatic and intestinal expression profiles of metabolic enzymes and transporters were analyzed using RNA-sequencing (RNA-Seq). Differential gene expression analysis was performed, with subsequent validation through quantitative real-time PCR (qPCR). A novel MAFLD population profile was developed in PK-Sim by integrating preclinical data with PBPK modeling parameters based on metabolic enzyme and transporter alterations.

Results: RNA-Seq and qPCR analyses revealed that Abcc2, Cyp2b9, Cyp2c38 and Cyp17a1 were upregulated by MAFLD in liver, whereas Slco1a1, Cyp2c29, Cyp3a11 and Cyp3a25 were downregulated. Intestinal expression changes were most pronounced for Slco10a2, Cyp3a11, and Ugt1a1. Cross-species analysis revealed strong correlations in drug transport and metabolism genes between murine and human tissues. PBPK modeling simulations predicted increased systemic exposure in MAFLD patients for drugs primarily metabolized by CYP2B6, CYP3A4, and CYP2C19. Interestingly, intestinal BCRP expression alterations in MAFLD showed minimal impact on drug exposure.

Conclusions: Closer monitoring of MAFLD patients receiving medications predominantly cleared by CYP 2B6, 3A4, and CYP2C19 is warranted to minimise toxicity risk. Further clinical investigations directly evaluating drug disposition in MAFLD patients are needed to confirm the modelling findings.

Keywords: MAFLD; Metabolic enzymes; Obesity; PBPK model; Transporters.