Repurposing ^99mTc-Mebrofenin as a Probe for Molecular Imaging of Hepatocyte Transporters

Hepatocyte transporters control the hepatobiliary elimination of many drugs, metabolites, and endogenous substances. Hepatocyte transporter function is altered in several pathophysiologic situations and can be modulated by certain drugs, with a potential impact for pharmacokinetics and drug-induced liver injury. The development of substrate probes with optimal properties for selective and quantitative imaging of hepatic transporters remains a challenge. ^99mTc-mebrofenin has been used for decades for hepatobiliary scintigraphy, but the specific transporters controlling its liver kinetics have not been characterized until recently. These include sinusoidal influx transporters (organic anion-transporting polypeptides) responsible for hepatic uptake of ^99mTc-mebrofenin, and efflux transporters (multidrug resistance-associated proteins) mediating its canalicular (liver-to-bile) and sinusoidal (liver-to-blood) excretion. Pharmacokinetic modeling enables molecular interpretation of ^99mTc-mebrofenin scintigraphy data, thus offering a widely available translational method to investigate transporter-mediated drug-drug interactions in vivo. ^99mTc-mebrofenin allows for phenotyping transporter function at the different poles of hepatocytes as a biomarker of liver function.