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

• Main Authors: Solène Marie (Author), Irene Hernández-Lozano (Author), Louise Breuil (Author), Charles Truillet (Author), Shuiying Hu (Author), Alex Sparreboom (Author), Nicolas Tournier (Author), Oliver Langer (Author)
• Format: Book
• Published: MDPI AG, 2021-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics13060918; 1999-4923
• Keywords: OATP2B1; drug transporters; [¹¹C]erlotinib; [^99mTc]mebrofenin; liver; imaging; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 13, Iss 6, p 918 (2021)

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 <i>Slco2b1^(-/-)</i> 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 <i>Slco2b1^(-/-)</i> 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 (<i>k</i>₂) and excreted bile (<i>k</i>₃). CL₁ was significantly reduced in <i>Slco2b1^(-/-)</i> mice for both radiotracers (<i>p</i> < 0.05), and <i>k</i>₂ was significantly lower (<i>p</i> < 0.01) in <i>Slco2b1^(-/-)</i> 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 <i>Slco2b1^(-/-)</i> 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.