Assessing drug-mediated inhibition of liver transporter function with MRI: A first-in-human study
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Background
Assessing the risk of drug-mediated liver injury (DILI) and liver-mediated drug-drug interactions (DDI) for new drugs requires biomarkers that respond to drug effects on hepatic transporters. Evidence in rats has shown that dynamic gadoxetate-enhanced MRI (DGE-MRI) is suitable for this purpose, but it is not known whether these findings translate to humans.
Purpose
To determine the effects of rifampicin, a known inhibitor of hepatocyte transporters OATP1B and MRP2, on gadoxetate uptake and excretion rates in the liver of healthy volunteers.
Materials and Methods
This prospective study recruited 10 healthy volunteers, who were assessed on two separate visits. DGE-MRI was performed over two separate scans, one hour apart, due to the slow hepatic excretion of gadoxetate after inhibition. DGE was acquired with a fast (2.5 sec) 3D free-breathing protocol collecting data continuously for 50 minutes. Gadoxetate was injected at 1/8 th of a clinical dose, escalated to 1/4 th after the first 3 volunteers. On the second visit, rifampicin (600mg) was administered orally one hour before the start of the scan. Liver uptake and excretion rates were derived by modelling signal-time curves in aorta and liver. The effect of rifampicin was determined with a paired t-test with significance level at p<0.01.
Results
Eight of the 10 participants (3 female/7 male, mean age 32) completed both visits. Rifampicin reduced hepatocellular uptake rate of gadoxetate by 93% (95%CI 91-95%, p<0.001). Biliary excretion rate was reduced by 50% (p=0.004) but the effect was more variable (95%CI 8- 92%). Both rates were reduced by rifampicin in every participant, except for the excretion rate of one participant who had low baseline levels.
Conclusion
MRI measurements of gadoxetate biliary excretion and liver uptake rates can robustly detect inhibition of hepatocellular function mediated via OATP1B and MRP2 transporters.
