Related Experiment Video

Updated: Jan 29, 2026

The Spared Nerve Injury SNI Model of Induced Mechanical Allodynia in Mice
07:44

The Spared Nerve Injury SNI Model of Induced Mechanical Allodynia in Mice

Published on: August 18, 2011

65.1K

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

Jeffrey L Woodhead1, Kyunghee Yang2, David Oldach3

  • 1DILIsym Services, Inc., a Simulations Plus Company, 6 Davis Drive, PO Box 12317, Research Triangle Park, North Carolina, 27709, USA. jwoodhead@dilisym.com.

Pharmaceutical Research
|February 9, 2019
PubMed
Abstract

Insights

Macrolide antibiotics can cause liver injury through different mechanisms, such as mitochondrial dysfunction or bile acid transporter inhibition. Quantitative systems pharmacology modeling helps reveal these distinct toxicity pathways for drug-induced liver injury (DILI).

Area of Science:

  • Pharmacology
  • Toxicology
  • Drug-induced liver injury (DILI)

Background:

  • Macrolide antibiotics are crucial for treating bacterial infections but can cause liver enzyme elevations.
  • Telithromycin, a macrolide, was withdrawn due to liver toxicity, highlighting the need to understand macrolide-induced hepatotoxicity.

Purpose of the Study:

  • To investigate the underlying mechanisms of liver toxicity associated with various macrolide antibiotics.
  • To differentiate the specific pathways leading to toxicity within the macrolide class.

Main Methods:

  • In vitro assays were used to evaluate bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress for five macrolides.
  • Quantitative systems pharmacology (QST) modeling (DILIsym) integrated in vitro data with predicted liver exposure to assess DILI risk.

Main Results:

  • Solithromycin and clarithromycin toxicity were linked to mitochondrial electron transport chain (ETC) inhibition.
  • Erythromycin toxicity was primarily associated with bile acid transporter inhibition.
  • DILIsym did not predict toxicity for telithromycin and azithromycin, suggesting potential unmodeled mechanisms or metabolite effects.

Conclusions:

  • Mechanisms of drug-induced liver injury vary significantly among structurally similar macrolide antibiotics.
  • Quantitative systems pharmacology (QST) modeling is a valuable tool for elucidating these mechanistic differences in drug toxicity.
Keywords:
BSEP inhibitionantibioticsliver injurymitochondriaquantitative systems toxicology

More Related Videos

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment08:59

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

Published on: December 3, 2020

8.6K
An Ex Vivo Laser-induced Spinal Cord Injury Model to Assess Mechanisms of Axonal Degeneration in Real-time11:18

An Ex Vivo Laser-induced Spinal Cord Injury Model to Assess Mechanisms of Axonal Degeneration in Real-time

Published on: November 25, 2014

11.4K

Related Concept Videos

Mechanical Systems01:22

Mechanical Systems

Mechanical systems are analogous to to electrical networks where springs and masses play similar roles to inductors and capacitors, respectively. A viscous damper in mechanical systems functions similarly to a resistor in electrical networks, dissipating energy. The forces acting on a mass in such systems include an applied force in the direction of motion, counteracted by forces from the spring, a viscous damper, and the mass's acceleration. This interplay of forces is mathematically...
636
Electro-mechanical Systems01:19

Electro-mechanical Systems

Electromechanical systems are intricate configurations that effectively combine electrical and mechanical elements to achieve a desired outcome. Central to many of these systems is the DC motor, a device that converts electrical energy into mechanical motion, enabling various applications ranging from simple fans to complex robotic mechanisms.
A key component of the DC motor is the armature, a rotating circuit positioned within a magnetic field. As an electric current passes through the...
1.7K
Antibiotic Selection00:57

Antibiotic Selection

Overview
59.9K
The Quantum-Mechanical Model of an Atom02:45

The Quantum-Mechanical Model of an Atom

Shortly after de Broglie published his ideas that the electron in a hydrogen atom could be better thought of as being a circular standing wave instead of a particle moving in quantized circular orbits, Erwin Schrödinger extended de Broglie’s work by deriving what is now known as the Schrödinger equation. When Schrödinger applied his equation to hydrogen-like atoms, he was able to reproduce Bohr’s expression for the energy and, thus, the Rydberg formula governing hydrogen spectra.
57.2K
Mechanisms of Retrovirus-induced Cancers01:51

Mechanisms of Retrovirus-induced Cancers

Retroviruses are RNA viruses that have been shown to cause cancers in diverse species, including chickens, mice, cats, and monkeys. The RNA genomes of these viruses are first reverse-transcribed into single and then double-stranded DNA (dsDNA) copies. This dsDNA called proviral DNA then integrates into the host genome. Subsequently, the host cell transcribes the proviral DNA in concert with the chromosomal DNA. This leads to the production of viral RNA and proteins that assemble at the host...
7.0K
Induced-fit Model01:13

Induced-fit Model

Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical...
89.1K