Isolated Perfused Rat Livers to Quantify the Pharmacokinetics and Concentrations of Gd-BOPTA.

Catherine M Pastor

doi:10.1155/2018/3839108

Abstract

With recent advances in liver imaging, the estimation of liver concentrations is now possible following the injection of hepatobiliary contrast agents and radiotracers. However, how these images are generated remains partially unknown. Most experiments that would be helpful to increase this understanding cannot be performed in vivo. For these reasons, we investigated the liver distribution of the magnetic resonance (MR) contrast agent gadobenate dimeglumine (Gd-BOPTA, MultiHance®, Bracco Imaging) in isolated perfused rat livers (IPRLs). In IPRL, we developed a new set up that quantifies simultaneously the Gd-BOPTA compartment concentrations and the transfer rates between these compartments. Concentrations were measured either by MR signal intensity or by count rates when the contrast agent was labelled by [153Gd]. With this experimental model, we show how the Gd-BOPTA hepatocyte concentrations are modified by temperature and liver flow rates. We define new pharmacokinetic parameters to quantify the canalicular transport of Gd-BOPTA. Finally, we present how transfer rates generate Gd-BOPTA concentrations in rat liver compartments. These findings better explain how liver imaging with hepatobiliary radiotracers and contrast agents is generated and improve the image interpretation by clinicians.

Highlights

In the past, great achievements were made by analysing the drug plasma concentrations to understand their body distribution
The coperfusion of the dye bromosulfophthalein (BSP) with Gd-BOPTA prevents the contrast agent entry into hepatocytes and the mean half-lives are similar to those measured with Gd-DTPA (Figures 3(a)–3(c)). is BSP inhibition of hepatocyte Gd-BOPTA uptake is the first drugdrug interaction evidenced by liver imaging
In the IPRL, we investigate two new parameters to assess multiple resistance-associated protein 2 (Mrp2) transport function: the gradients between Gd-BOPTA hepatocyte and bile concentrations over the perfusion period, and a unique parameter named canalicular concentration ratio (CCR) that represents the slope of the nonlinear regression curve between hepatocyte and bile concentrations [15]

Summary

Introduction

Great achievements were made by analysing the drug plasma concentrations to understand their body distribution. Erefore, when conducting pharmacokinetic studies, it was assumed that hepatocyte concentrations approximate plasma concentrations, the drug equilibration across the sinusoidal membrane being obtained by passive di usion. To study more speci cally the activity of hepatocyte transporters in vivo, radiotracers for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging and gadolinium complexes for magnetic resonance imaging (MRI) can be injected before the image acquisition [1,2,3,4]. How these images are generated remains partially unknown.

Methods

Results

Conclusion