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

Area of Science:

• Pharmacology
• Hepatology
• Drug Metabolism

Background:

• Organic anion-transporting polypeptides (OATPs) are crucial for hepatic drug uptake.
• OATP2B1, along with OATP1B1 and OATP1B3, is located in the basolateral hepatocyte membrane.
• Understanding the specific roles of individual OATPs, like OATP2B1, is vital for predicting drug disposition.

Purpose of the Study:

• To characterize a novel Slco2b1 knockout mouse model (Slco2b1^(-/-)).
• To evaluate the hepatic uptake of [11C]erlotinib and [99mTc]mebrofenin in wild-type and Slco2b1^(-/-) mice using PET and scintigraphic imaging.
• To assess the contribution of OATP2B1 to the hepatic uptake of drugs.

Main Methods:

• Generation and characterization of Slco2b1^(-/-) mice.
• Positron emission tomography (PET) imaging with [11C]erlotinib.
• Planar scintigraphic imaging with [99mTc]mebrofenin.
• Pharmacokinetic modeling to determine hepatic uptake clearance (CL1) and rate constants (k2, k3).

Main Results:

• Hepatic uptake clearance (CL1) was significantly reduced in Slco2b1^(-/-) mice for both [11C]erlotinib and [99mTc]mebrofenin.
• The rate constant for transfer from liver to blood (k2) was significantly lower for [11C]erlotinib in Slco2b1^(-/-) mice.
• No significant difference in k2 was observed for [99mTc]mebrofenin between genotypes.

Conclusions:

• OATP transporters likely contribute to the hepatic uptake of [11C]erlotinib.
• The reduced uptake of [99mTc]mebrofenin (an OATP1B1/1B3 substrate) in Slco2b1^(-/-) mice raises questions about the model's specificity.
• The utility of this Slco2b1^(-/-) mouse model for assessing OATP2B1's role in drug uptake, especially for substrates of multiple OATPs, needs further investigation.