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 (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.

Humanization ofSLCO2B1in Rats Increases rCYP3A1 Protein Expression but Not the Metabolism of Erlotinib to OSI-420

“…2). This particular finding is in accordance with the assumption that erlotinib is a substrate of the human transporter (Bauer et al, 2018) and that OATP2B1 contributes to the hepatic uptake of the tyrosine kinase inhibitor in rodents and humans (Amor et al, 2018;Bauer et al, 2018;Marie et al, 2021). However, there was no change in the OSI-420/erlotinib ratio in the serum samples, suggesting that there is no difference in metabolism of erlotinib in our rat models.…”

“…Moreover, the tyrosine kinase inhibitor is a substrate of OATP2B1 (Bauer et al, 2018) and has previously been investigated in genetically modified mouse models. In a PET-study with [ 11 C]-erlotinib, mSlco2b1 À/À mice showed a reduced hepatic uptake clearance, however, with unchanged concentrations in blood (Marie et al, 2021). In another work, Li et al (2023) studied the pharmacokinetics of erlotinib and OSI-420 after oral administration in genetically modified mice.…”

Influence of Slco2b1‐knockout and SLCO2B1‐humanization on coproporphyrin I and III levels in rats

“…Notably, there are mOATP2B1-deficient mouse models available that have been investigated for the influence of the transporter on the in vivo disposition of erlotinib, fexofenadine, fluvastatin and rosuvastatin (Chen et al, 2020;Marie et al, 2021;Medwid et al, 2019).…”

“…Notably, there are mOATP2B1‐deficient mouse models available that have been investigated for the influence of the transporter on the in vivo disposition of erlotinib, fexofenadine, fluvastatin and rosuvastatin (Chen et al, 2020; Marie et al, 2021; Medwid et al, 2019). Even though the murine data support a function of the transporter as a determinant of its substrates' pharmacokinetics by influencing oral absorption and hepatic clearance, there is still a need for further investigations including the impact of OATP2B1 on CP levels.…”