Research Article: Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography

Date Published: April 29, 2019

Publisher: Springer International Publishing

Author(s): Irene Hernández Lozano, Rudolf Karch, Martin Bauer, Matthias Blaickner, Akihiro Matsuda, Beatrix Wulkersdorfer, Marcus Hacker, Markus Zeitlinger, Oliver Langer.

http://doi.org/10.1208/s12248-019-0323-0

Abstract

Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [11C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [11C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300 mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment (4C) model, in which either a sampled arterial blood input function or a mathematically derived dual input function (DIF), which takes the contribution of the portal vein to the liver blood supply into account, was used. Both models provided acceptable fits of the observed PET data in the liver and extrahepatic bile duct and gall bladder. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [11C]erlotinib. Our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in drug-drug interactions.

Partial Text

The liver is the major organ responsible for the metabolism and excretion of xenobiotics. It expresses several different transport proteins belonging to the solute carrier (SLC) and ATP-binding cassette (ABC) families in both the blood-facing basolateral membrane and in the bile-facing canalicular membrane of hepatocytes. These transporters regulate the uptake and biliary secretion of drugs and their metabolites into and out of the hepatocytes and therefore play a key role in the clearance of drugs (1). In addition to drug metabolizing enzymes, transporters can be involved in drug-drug interactions (DDIs). For instance, co-administration of a drug which is a substrate and a drug which is an inhibitor of the same transporter(s) can lead to changes in the pharmacokinetics (PK) of the substrate drug making transporters a potential source of PK variability (2).

To advance the applicability of PET imaging as an upcoming tool in the study of hepatic transporter function, we evaluated different compartment modeling approaches for the analysis of previously acquired human PET data with [11C]erlotinib (18,19), which we considered as a small-molecule drug model, which undergoes transporter-mediated hepatobiliary excretion.

We developed 3C and 4C models to describe the kinetics of [11C]erlotinib in the hepatobiliary system. Both the models provided acceptable fits of the observed data, but the 4C model provided a richer kinetic picture, including an additional compartment that represented the radiotracer disposition in the intrahepatic bile duct that was not visible in the PET scan but also accounted for the total liver radioactivity. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [11C]erlotinib. Contrary to our expectations, our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. However, the benefit of a DIF may depend on the radiotracer being employed, so that future efforts should be directed towards defining improved algorithms for partial volume and motion correction of image-derived PV input functions in humans. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in DDIs.

 

Source:

http://doi.org/10.1208/s12248-019-0323-0

 

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