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

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 (CL ₁) and the rate constants for transfer of radioactivity from the liver to the blood ( k ₂) and excreted bile ( k ₃). CL ₁ was significantly reduced in Slco2b1 ^(-/-) mice for both radiotracers ( p < 0.05), and k ₂ 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.