DOI: 10.5281/zenodo.15610350
title: Drug-mediated inhibition of liver transporters: results from TRISTAN gadoxetate MRI studies

description: Database

This database collects measurements of liver transporter function derived from kinetic liver data measured with gadoxetate-enhanced MRI. The results were derived through a series of experiments by the liver workpackage of the TRISTAN consortium. The database is maintained by the open medical imaging biomarkers laboratory (miblab.org).

Subjects

Human healthy volunteers, patients and rats.

Background

The data are taken from a series of preclinical and clinical studies performed by the TRISTAN project, in the period 2018-2024. The aim of these studies was to test if the effect of drugs on uptake and excretory function of the liver can be measured reliably with dynamic gadoxetate-enhanced MRI. Combined these studies provide proof of concept for a new MRI-based biomarker to predict the risk of liver-mediated drug-drug interactions, and of drug-induced liver injury. 

The data have been used to support a submission to the FDA's biomarker qualification program (details).

Format

All data are in dmr format - a folder with three csv files:



data.csv: Data dictionary

rois.csv: ROI curves

pars.csv: Subject parameters


The data can be read and manipulated interactively with common applications such as excel, or programmatically with the python package pydmr. 

Datasets

tristan_humans_healthy_rifampicin_all_results

The data were acquired in the aorta and liver of 8 healthy volunteers with dynamic gadoxetate-enhanced MRI, before and after administration of a drug (rifampicin) which is known to inhibit liver function. The assessments were done on two separate visits at least 2 weeks apart. On each visit, the volunteer had two scans each with a separate contrast agent injection of a quarter dose each. the scans were separated by a gap of about 1 hour to enable gadoxetate to clear from the liver. This design was deemed necessary for reliable measurement of excretion rate when liver function was inhibited.

The research question was to what extent rifampicin inhibits gadoxetate uptake rate from the extracellular space into the liver hepatocytes (khe, mL/min/100mL) and excretion rate from hepatocytes to bile (kbh, mL/100mL/min). 2 of the volunteers only had the baseline assessment, the other 8 volunteers completed the full study. The results showed consistent and strong inhibition of khe (95%) and kbh (40%) by rifampicin. This implies that rifampicin poses a risk of drug-drug interactions (DDI), meaning it can cause another drug to circulate in the body for far longer than expected, potentially causing harm or raising a need for dose adjustment.

 





Please reference the following abstract when using these data (manuscript in preparation):

 


Thazin Min, Marta Tibiletti, Paul Hockings, Aleksandra Galetin, Ebony Gunwhy, Gerry Kenna, Nicola Melillo, Geoff JM Parker, Gunnar Schuetz, Daniel Scotcher, John Waterton, Ian Rowe, and Steven Sourbron. Measurement of liver function with dynamic gadoxetate-enhanced MRI: a validation study in healthy volunteers. Proc Intl Soc Mag Reson Med, Singapore 2024.


tristan_humans_healthy_metformin_all_results

 

Data from a similar experiment as the rifampicin study in healthy volunteers, but with the drug metformin and performed in another center with a different scanner vendor. The study includes 6 volunteers.

 

The variables are the same as in the rifampicin study.

 



Manuscript in preparation.


 



tristan_humans_healthy_ciclosporin_all_results

 

Data from a similar experiment as the metformin study in healthy volunteers, but with the drug ciclosporin. 

 

The variables are the same as in the rifampicin study.

 



Manuscript in preparation.


 



tristan_humans_healthy_controls_all_results

 

Five subjects enrolled in the rifampicin, metformin and ciclosporin studies had their baseline assessment but did not go on to have the the treatment visit, for various reasons. These data are combined together in this file. They can be added to the baseline data of the other studies to form a control cohort.




tristan_humans_patients_rifampicin_all_results

 
The study aimed to demonstrates the effect of rifampicin on liver function of patients with impaired function.

 

The data were acquired in the aorta and liver in 3 patients with dynamic gadoxetate-enhanced MRI. The study participants take rifampicin as part of their routine clinical workup, with an aim to promote their liver function. For this study, they were taken off rifampicin 3 days before the first scan, and placed back on rifampicin 3 days before the second scan. The aim was to determine the effect if rifampicin in uptake and excretion function of the liver.

The data confirmed that patients had significantly reduced uptake and excretion function in the absence of rifampicin. Rifampicin administration improved their excretory function but had no effect on their uptake function.

 

The variables are the same as in the rifampicin study in healthy volunteers, but the patient study was performed in a different center.

 

Manuscript in preparation.