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

BackgroundUnderstanding the impact of altered hepatic uptake and/or efflux on the hepatobiliary disposition of the imaging agents [Tc-99m]Mebrofenin (MEB) and [Gd-153]Gadobenate dimeglumine (BOPTA) is important for proper estimation of liver function.MethodsA 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).ResultsThe model adequately described MEB and BOPTA disposition in each compartment. The hepatocyte uptake clearance was much higher for MEB (55.3 mL/min) than BOPTA (6.67 mL/min), whereas the sinusoidal efflux clearance for MEB (0.000831 mL/min) was lower than BOPTA (0.0127 mL/min). The clearance from hepatocytes to bile (CLbc) for MEB (0.658 mL/min) was similar to BOPTA (0.642 mL/min) in healthy rat livers. The BOPTA CLbc was reduced in livers from MCT-pretreated rats (0.496 mL/min), while the sinusoidal efflux clearance was increased (0.0644 mL/min).ConclusionA 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.

Automated summary

In this study, a multi-compartmental pharmacokinetic (PK) model was developed to describe the hepatic disposition of two imaging agents in normal and liver-damaged rats. The results showed differential uptake and efflux rates between the two agents in hepatocytes and extracellular space. This PK model could be used to assess changes in hepatic uptake and efflux of these imaging agents in response to disease, toxicity, or drug-drug interactions.