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

Solène Marie,Alex Sparreboom,Nicolas Tournier,Irene Hernández-Lozano,Oliver Langer,Shuiying Hu,Charles Truillet,Louise Breuil

doi:10.3390/pharmaceutics13060918

Abstract

Organic anion-transporting polypeptide 2B1 (OATP2B1) is co-localized with OATP1B1 and OATP1B3 in the basolateral hepatocyte membrane, where it is thought to contribute to the hepatic uptake of drugs. We characterized a novel Slco2b1(-/-) mouse model using positron emission tomography (PET) imaging with [11C]erlotinib (a putative OATP2B1-selective substrate) and planar scintigraphic imaging with [99mTc]mebrofenin (an OATP1B1/1B3 substrate, which is not transported by OATP2B1). Dynamic 40-min scans were performed after intravenous injection of either [11C]erlotinib or [99mTc]mebrofenin in wild-type and Slco2b1(-/-) mice. A pharmacokinetic model was used to estimate the hepatic uptake clearance (CL1) and the rate constants for transfer of radioactivity from the liver to the blood (k2) and excreted bile (k3). CL1 was significantly reduced in Slco2b1(-/-) mice for both radiotracers (p < 0.05), and k2 was significantly lower (p < 0.01) in Slco2b1(-/-) mice for [11C]erlotinib, but not for [99mTc]mebrofenin. Our data support previous evidence that OATP transporters may contribute to the hepatic uptake of [11C]erlotinib. However, the decreased hepatic uptake of the OATP1B1/1B3 substrate [99mTc]mebrofenin in Slco2b1(-/-) mice questions the utility of this mouse model to assess the relative contribution of OATP2B1 to the liver uptake of drugs which are substrates of multiple OATPs.

Highlights

Mouse showed that, after i.v. injection of [11 C]erlotinib, radioactivity was rapidly taken up into the liver followed by excretion into the intestine (Figure 1)
Organic anion-transporting polypeptides (OATPs) transporter but shows a wide tissue distribution profile, we investigated the effect of Slco2b1 knockout on the distribution of [11 C]erlotinib to other tissues with known
Employment of a liver PK model revealed a significant decrease in the hepatic uptake clearance (CL1 ) of both radiotracers in Slco2b1(-/-) mice

Summary

Introduction

Organic anion-transporting polypeptides (OATPs) belong to the solute carrier (SLC). Superfamily of transporters and are involved in the tissue uptake of endogenous compounds and many clinically used drugs [1]. OATP2B1 (encoded by the SLCO2B1 gene) is one important member of the OATP family and has a rather broad tissue expression profile including the small intestine, liver, kidneys, brain, heart, lungs and skeletal muscle [2,3,4,5,6]. Several drugs have been identified in vitro as substrates of OATP2B1, which is believed to be involved in the intestinal absorption of orally administered drugs. Relevant OATP2B1-mediated food–drug interactions have been reported with certain fruit

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