Comparison of drug-induced liver injury risk between propylthiouracil and methimazole: A quantitative systems toxicology approach

• Published in: Toxicology and applied pharmacology 2024-10, Vol.491, p.117064, Article 117064
• Main Authors: He, Qingfeng, Li, Min, Ji, Peiying, Zheng, Aole, Yao, Li, Zhu, Xiao, Shin, Jae-Gook, Lauschke, Volker M., Han, Bing, Xiang, Xiaoqiang
• Format: Article
• Language: English
• Subjects: Animals; Antithyroid Agents - toxicity; Cell Survival - drug effects; Chemical and Drug Induced Liver Injury - etiology; DILIsym; Drug induced livery injury; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Liver - drug effects; Liver - metabolism; Medicin och hälsovetenskap; Methimazole; Methimazole - toxicity; Models, Biological; Oxidative Stress - drug effects; Physiologically based pharmacokinetic model; Propylthiouracil; Propylthiouracil - pharmacokinetics; Propylthiouracil - toxicity; Quantitative systems toxicology; Risk Assessment
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2024.117064

Propylthiouracil (PTU) and methimazole (MMI), two classical antithyroid agents possess risk of drug-induced liver injury (DILI) with unknown mechanism of action. This study aimed to examine and compare their hepatic toxicity using a quantitative system toxicology approach. The impact of PTU and MMI on hepatocyte survival, oxidative stress, mitochondrial function and bile acid transporters were assessed in vitro. The physiologically based pharmacokinetic (PBPK) models of PTU and MMI were constructed while their risk of DILI was calculated by DILIsym, a quantitative systems toxicology (QST) model by integrating the results from in vitro toxicological studies and PBPK models. The simulated DILI (ALT >2 × ULN) incidence for PTU (300 mg/d) was 21.2%, which was within the range observed in clinical practice. Moreover, a threshold dose of 200 mg/d was predicted with oxidative stress proposed as an important toxic mechanism. However, DILIsym predicted a 0% incidence of hepatoxicity caused by MMI (30 mg/d), suggesting that the toxicity of MMI was not mediated through mechanism incorporated into DILIsym. In conclusion, DILIsym appears to be a practical tool to unveil hepatoxicity mechanism and predict clinical risk of DILI. [Display omitted] •Utilized quantitative systems toxicology models to reveal key mechanisms for DILI.•Predicted DILI incidence of propylthiouracil and methimazole at clinical regimens.•Addressed needs for further mechanism investigation on methimazole hepatoxicity.