Toxic liver effects of fifteen drugs predicted using computational approach

February 2, 2017, Public Library of Science
Multiscale analysis of drug-induced cellular responses. The application of a multiscale modeling approach in humans allows the representation of drug concentration-time profiles in liver tissue and ultimately enables a comparative analysis of simulated drug-induced changes at the cellular scale. Credit: Thiel, Kuepfer

A team of researchers has used a computational modeling approach to analyze and compare the toxic effects of fifteen different drugs on the liver, according to a study in PLOS Computational Biology.

Drugs prescribed for various medical conditions can cause harmful side effects. Lab experiments with can help reveal the underlying molecular mechanisms by which these drugs cause , which could inform better prevention and treatment efforts. However, alone cannot reliably predict actual effects in living patients.

To improve translation of lab data to patients, Christoph Thiel of RWTH Aachen University, Germany, and colleagues recently developed a new strategy that uses computational modeling to simulate how liver cells in the body respond to different doses of different drugs. The approach integrates experimental observations with knowledge of how drugs are distributed and metabolized after they enter the body.

The researchers had previously demonstrated their approach in a proof-of-concept study. In the new study, the approach was applied to simulate and compare the potentially toxic liver effects of fifteen different drugs at clinically relevant doses.

The scientists developed whole-body models to simulate the fate of each drug after ingestion and validated the models using experimental data from scientific literature. These models were then coupled with lab data to predict each drug's effects on the liver at patient level. The researchers found that the drugs fell into different groups that caused similar responses, including which genes would be transcribed in response to toxic doses.

While further validation is required, the method has the potential to lead to faster diagnosis of toxic liver side effects in patients. It could help reveal which gene transcripts could serve as early signs of toxicity and which combinations might be particularly dangerous, for both new and existing drugs.

"Consistently applied to the design of clinical development programs, the approach presented has the potential to early identify medical and economic risks of new drugs," says study co-author Lars Kuepfer.

Explore further: Paracetamol study could open door for way to treat liver damage

More information: Thiel C, Cordes H, Fabbri L, Aschmann HE, Baier V, Smit I, et al. (2017) A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations. PLoS Comput Biol 13 (2): e1005280. DOI: 10.1371/journal.pcbi.1005280

Related Stories

Paracetamol study could open door for way to treat liver damage

January 31, 2017
Scientists have shed new light on how the common painkiller paracetamol causes liver damage.

Gene therapy for metabolic liver diseases shows promise in pigs

July 27, 2016
With a shortage of donor organs, Mayo Clinic is exploring therapeutic strategies for patients with debilitating liver diseases. Researchers are testing a new approach to correct metabolic disorders without a whole organ transplant. ...

Unexpected activity of two enzymes helps explain why liver cancer drugs fail

December 13, 2016
Some cancers are caused by loss of enzymes that should keep cell growth in check. On the flip side, some are caused by over-activation of enzymes that enhance cell growth. Yet drugs that inhibit the overactive enzymes have ...

Molecular 'pillars' team up to protect liver from toxic fat buildup

November 18, 2016
As obesity rates rise in the United States, so does the incidence of liver diseases. In fact, 80 percent of obese people are believed to have non-alcoholic fatty liver disease, or NAFLD, while another related liver disorder, ...

Recommended for you

BPA can induce multigenerational effects on ability to communicate

June 18, 2018
Past studies have shown that biparental care of offspring can be affected negatively when females and males are exposed to bisphenol A (BPA); however, previous studies have not characterized how long-term effects of BPA exposure ...

New compound shown to be as effective as FDA-approved drugs against life-threatening infections

June 15, 2018
Purdue University researchers have identified  a new compound that in preliminary testing has shown itself to be as effective as antibiotics approved by the Food and Drug Administration to treat life-threatening infections ...

Foods combining fats and carbohydrates more rewarding than foods with just fats or carbs

June 14, 2018
Researchers show that the reward center of the brain values foods high in both fat and carbohydrates—i.e., many processed foods—more than foods containing only fat or only carbs. A study of 206 adults, to appear June ...

3-D imaging and computer modeling capture breast duct development

June 14, 2018
Working with hundreds of time-lapse videos of mouse tissue, a team of biologists joined up with civil engineers to create what is believed to be the first 3-D computer model to show precisely how the tiny tubes that funnel ...

Beating cancer at its own game with a Trojan horse telomerase

June 13, 2018
Telomerase is a reverse transcriptase that uses an RNA template to synthesize telomeres. These repeat sequences bind special proteins that fold the ends of chromosomes back onto themselves to create a stable cap. When this ...

Turning the tables on the cholera pathogen

June 13, 2018
Recent cholera outbreaks in regions that are ravaged by war, struck by natural disasters, or simply lack basic sanitation, such as Yemen or Haiti, are making the development of new and more effective interventions a near-term ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.