Oral Administration of [¹⁸F]MC225 for Quantification of P-glycoprotein Function: A Feasibility Study

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 [¹⁸F]MC225. Different oral administration protocols were evaluated, and radioactivity uptake was compared with uptake following intravenous administration.

Twelve male Wistar rats were divided into four groups and subjected to intravenous or oral [¹⁸F]MC225 administration protocols: G₁ (intravenous route), G₂ (oral administration without fasting), G₃ (oral administration with fasting), and G₄ (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.

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 [¹⁸F]MC225 in the GI tract. Metabolite analysis in G₄ indicated a significant presence of polar metabolites.

Oral administration of [¹⁸F]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.