Analyzing the Mechanisms Behind Macrolide Antibiotic-Induced Liver Injury Using Quantitative Systems Toxicology Modeling

Authors: Woodhead JL, Yang K, Oldach D, MacLauchlin C, Fernandes P, Watkins PB, Siler SQ, Howell BA
Publication: Pharm Res
Keywords: antibiotics, BSEP inhibition, Cempra, drug induced liver injury (DILI), hepatotoxicity, liver injury, macrolides, mitochondria, QSP (quantitative systems pharmacology) modeling program, Quantitative Systems Toxicology (QST), solithromycin, telithromycin, toxicology
Software: DILIsym®
Division: DILIsym Services

Abstract

Purpose

Macrolide antibiotics are commonly prescribed treatments for drug-resistant bacterial infections; however, many macrolides have been shown to cause liver enzyme elevations and one macrolide, telithromycin, has been pulled from the market by its provider due to liver toxicity. This work seeks to assess the mechanisms responsible for the toxicity of macrolide antibiotics.

Methods

Five macrolides were assessed in in vitro systems designed to test for bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress. The macrolides were then
represented in DILIsym, a quantitative systems pharmacology (QST) model of drug-induced liver injury, placing the in vitro
results in context with each compound’s predicted liver exposure and known biochemistry.

Results

DILIsym results suggest that solithromycin and clarithromycin toxicity is primarily due to inhibition of the mitochondrial electron transport chain (ETC) while erythromycin toxicity is primarily due to bile acid transporter inhibition. Telithromycin and azithromycin toxicity was not predicted by DILIsym and may be caused by mechanisms notcurrently incorporated into DILIsym or by unknown metabolite effects.

By Jeffrey Woodhead, Kyunghee Yang, Paul Watkins, Scott Q Siler, and Brett Howell