Oral Administration of [F]MC225 for Quantification of P-glycoprotein Function: A Feasibility Study.

Purpose: This preclinical study explored the feasibility of assessing P-glycoprotein (P-gp) function in both brain and gastrointestinal (GI) tract of rats using positron emission tomography (PET) following oral administration of [F]MC225. Different oral administration protocols were evaluated, and radioactivity uptake was compared with uptake following intravenous administration.

Procedures: Twelve male Wistar rats were divided into four groups and subjected to intravenous or oral [F]MC225 administration protocols: G (intravenous route), G (oral administration without fasting), G (oral administration with fasting), and G (oral administration with fasting following administration of the P-gp inhibitor tariquidar). Dynamic brain imaging, late abdominal imaging, ex vivo biodistribution, and metabolite analysis were conducted to assess tracer distribution.

Results: In the brain, oral administration yielded lower values compared with intravenous administration, resulting in a reduction in the tissue-to-plasma ratio by approximately 51% for the cortex and 45% for the midbrain and cerebellum. Fasting improved radioactivity uptake, aiding brain visualization. Unexpectedly, administration of the P-gp inhibitor tariquidar did not increase brain concentration, suggesting a signal that was dominated by non-specific uptake, possibly due to instability of [F]MC225 in the GI tract. Metabolite analysis in G indicated a significant presence of polar metabolites.

Conclusions: Oral administration of [F]MC225 faces challenges and, at this stage, cannot be used to quantify P-gp function. Further research to assess tracer stability and metabolism in the stomach and intestine will be essential for advancing the feasibility of oral tracer administration.