Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor

Previously published digital autoradiography of (3)H‐labeled capecitabine reveals a near‐uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to (14)C‐labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood to inhibit drug penetration. Capecitabine is a pro‐drug for 5 FU. The positioning of the radiolabel on capecitabine leaves open the possibility that much of the autoradiographic signal is generated by nontoxic compounds. Studies were performed on tumors derived via organoid culture from a murine KPC tumor. As before, we performed autoradiography comparing (3)H capecitabine to the gemcitabine analog (18)F‐FAC. The metabolism of capecitabine in this model was studied through LC–MS of tumor tissue. The autoradiographs confirmed that the (3)H label from capecitabine was much more uniformly distributed through the tumor than the (18)F from the gemcitabine analog. LC–MS revealed that approximately 75% of the molar mass of capecitabine had been converted into 5 FU or pre‐5 FU compounds. The remainder had been converted into nontoxic species. Therapeutically relevant capecitabine metabolites achieve a relatively even distribution in this pancreatic cancer model, in contrast to the gemcitabine analog (18)F‐FAC. In a human xenograft model, (BxPC3), the (3)H label from capecitabine was also uniformly spread across the tumor autoradiographs. However, at 2 h post‐administration the metabolism of capecitabine had proceeded further and the bulk of the agent was in the form of nontoxic species.