Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by ¹¹C-Cholylsarcosine PET

Abstract

The aim of this study was to develop a method for the quantification of hepatobiliary uptake and secretion of conjugated bile acids with PET and the 11 C-labeled conjugated bile acid analog [N-methyl-11 C] cholylsarcosine ( 11 C-CSar). Methods: Six pigs (13 experiments) underwent dynamic 11 C-CSar PET of the liver with simultaneous measurements of hepatic blood perfusion and 11 C-CSar concentrations in arterial, portal, and hepatic venous blood. In 3 pigs (7 experiments), bile was collected from a catheter in the common hepatic duct. PET data were analyzed with a 2-tissue compartmental model with calculation of rate constants for the transport of 11 C-CSar among blood, hepatocytes, and intra-and extrahepatic bile ducts. PET results were validated against invasive blood and bile measurements. Results: The directly measured rate of secretion of 11 C-CSar into bile was equal to the rate of removal from blood at steady state. Accordingly, hepatocytes did not accumulate bile acids but simply facilitated the transport of bile acids from blood to bile against a measured concentration gradient of 4,000. The rate constant for the secretion of 11 C-CSar from hepatocytes into bile in experiments with a catheter in the common hepatic duct was 25% of that in experiments without a catheter (P , 0.05); we interpreted this result to be mild cholestasis caused by the catheter. The catheter caused an increased backflux of 11 C-CSar from hepatocytes to blood, and hepatic blood flow was 25% higher than in experiments without the catheter. The capacity for the overall transport of 11 C-CSar from blood to bile, as quantified by intrinsic clearance, was significantly lower in experiments with the catheter than in those without the catheter (P , 0.001). PET and blood measurements correlated significantly (P , 0.05). Conclusion: The in vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic 11 C-CSar PET.

The ascending pathophysiology of cholestatic liver disease

“…Pharmacokinetic tests to detect impairment of hepatobiliary secretion, using 11 C–labeled BS derivatives and dynamic positron emission tomographic scanning, need to be studied in a clinical setting . For staging of biliary strictures in PSC and bile duct lesions in PBC, 3D reconstructions of liver specimens could yield important information.…”

“…need to be studied in a clinical setting. (68) For staging of biliary strictures in PSC and bile duct lesions in PBC, 3D reconstructions of liver specimens could yield important information.…”

Imaging techniques to study drug transporter function in vivo

“…Therefore, modeling approaches either have to rely on image-derived portal blood curves, which may be prone to imaging artefacts due to the small size of the investigated structures, or on data acquired in preclinical species (e.g. pigs) in which portal blood can be sampled (Ørntoft et al, 2017;Sørensen et al, 2016). Figure 3 shows a kinetic model used for quantification of hepatic disposition of the radiolabeled bile acid [ 11 C]cholylsarcosine in humans (Ørntoft et al, 2017).…”

Progress in the Molecular Characterization of Hepatobiliary Transporters

“…In the meantime, these transporters provide a molecular basis for our understanding of the compensatory basolateral efflux of bile acids and many conjugates under cholestatic conditions [13] . Functionally, this basolateral efflux has been observed early and noninvasively by positron-emission tomography in rats using the physiological leukotriene 11 C-N-acetyl-leukotriene E 4 [14] , in the isolated perfused rat liver using dibromosulfophthalein [15] , and recently by positron-emission tomography using the bile acid analog 11 C-cholylsarcosine in pigs [16] and humans [17] .…”