Application of Pharmacokinetic Modeling to Characterize Hepatobiliary Disposition of Imaging Agents and Alterations due to Liver Injury in Isolated Perfused Rat Livers.

Abstract

Understanding the impact of altered hepatic uptake and/or efflux on the hepatobiliary disposition of the imaging agents [99mTc]Mebrofenin (MEB) and [153Gd]Gadobenate dimeglumine (BOPTA) is important for proper estimation of liver function. A multi-compartmental pharmacokinetic (PK) model describing MEB and BOPTA disposition in isolated perfused rat livers (IPRLs) was developed. The PK model was simultaneously fit to MEB and BOPTA concentration-time data in the extracellular space, hepatocytes, bile canaliculi, and sinusoidal efflux in livers from healthy rats, and to BOPTA concentration-time data in rats pretreated with monocrotaline (MCT). The model adequately described MEB and BOPTA disposition in each compartment. The hepatocyte uptake clearance was much higher for MEB (55.3mL/min) than BOPTA (6.67mL/min), whereas the sinusoidal efflux clearance for MEB (0.000831mL/min) was lower than BOPTA (0.0127mL/min). The clearance from hepatocytes to bile (CLbc) for MEB (0.658mL/min) was similar to BOPTA (0.642mL/min) in healthy rat livers. The BOPTA CLbc was reduced in livers from MCT-pretreated rats (0.496mL/min), while the sinusoidal efflux clearancewas increased (0.0644mL/min). A PK model developed to characterize MEB and BOPTA disposition in IPRLs was used to quantify changes in the hepatobiliary disposition of BOPTA caused by MCT pretreatment of rats to induce liver toxicity. This PK model could be applied to simulate changes in the hepatobiliary disposition of these imaging agents in rats in response to altered hepatocyte uptake or efflux associated with disease, toxicity, or drug-drug interactions.