Use of imaging to assess the activity of hepatic transporters

Abstract

Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available. Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach. Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs. ARTICLE HISTORY

Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats

“…Efforts are being made to develop imaging protocols for selective determination of the respective importance of each transporter system in vivo [ 40 ]. Several small-molecule probes for Positron Emission Tomography (PET) have been proposed to study OATP transporter activity and to assess the interplay between sinusoidal uptake and canalicular efflux in vivo [ 13 , 19 , 40 ]. However, imaging protocols for selective determination of MRP2 activity at the canalicular interface are currently not available.…”

“…In vitro hepatocytes or in situ rodent liver perfusion have convincingly demonstrated the importance of canalicular MRP2 activity in controlling the liver-to-bile gradient [ 11 , 12 ]. Dynamic imaging methods using transporter probe substrates are being developed to study liver transporter activity in vivo [ 13 , 14 ]. Ideal imaging probes have to survive hepatic metabolism to avoid the generation of radiolabeled metabolites, which may confound the interpretation of the imaging data [ 14 ].…”

Imaging-Based Characterization of a Slco2b1(-/-) Mouse Model Using [11C]Erlotinib and [99mTc]Mebrofenin as Probe Substrates

“…This approach has been termed as PK imaging and has proven suitable to assess the influence of membrane transporters on drug tissue distribution and excretion [ 14 ]. With dynamic acquisition and dedicated compartmental PK models, quantitative parameters describing drug transfer across biological membranes can be obtained, which can be related to the activity of different membrane transporters [ 15 , 16 , 17 ].…”

Assessing the Functional Redundancy between P-gp and BCRP in Controlling the Brain Distribution and Biliary Excretion of Dual Substrates with PET Imaging in Mice

“…In addition, integration plot analysis has previously been applied to assess the influence of P-gp and BCRP on the biliary excretion of [ 11 C]erlotinib in mice [ 16 ]. Although integration plot analysis provided similar results for [ 11 C]erlotinib as in this study, it does not provide a complete picture of the hepatobiliary disposition of a radiotracer [ 10 ]. Moreover, the liver PK model used in this study considers the dual blood input to the liver via the portal vein and the hepatic artery.…”

“…On the other hand, small-animal PET imaging in mice offers the possibility to simultaneously and dynamically measure the whole-body disposition of radiolabeled molecules. In combination with suitable PK models, quantitative parameters can be obtained that can be related to membrane transporter activity in different organs [ 10 ]. The carbon-11 ( 11 C)-labeled third-generation P-gp inhibitors [ 11 C]tariquidar and [ 11 C]elacridar and the tyrosine kinase inhibitor [ 11 C]erlotinib are dual P-gp and BCRP substrates [ 6 , 7 , 11 ] and have been used to assess the activity of P-gp and BCRP at the human and mouse BBB [ 7 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”