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

Pharmaceutics

Oliver Langer¹  Irene Hernández-Lozano¹  Shuiying Hu²  Alex Sparreboom²  Solène Marie³  Charles Truillet³  Nicolas Tournier³  Louise Breuil³ 

[1] Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, CEA, CNRS, Inserm, 4 Place du Général Leclerc, 91401 Orsay, France;

关键词: OATP2B1;    drug transporters;    [¹¹C]erlotinib;    [^99mTc]mebrofenin;    liver;    imaging;   

DOI  :  10.3390/pharmaceutics13060918

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown