Inhibition of fluoropyrimidine catabolism by benzyloxybenzyluracil. Possible relevance to regional chemotherapy

Regional infusion with fluoropyrimidines is useful in the treatment of hepatic metastases. However, the effectiveness of regional infusion is minimized by rapid degradation of 5-fluorouracil (FUra) and 5-fluoro-2′-deoxyuridine (FdUrd) by the liver which limits the availability of drug for anabolism to active metabolites. 5-Benzyloxybenzyluracil (BBU) is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), the initial enzyme in FUra catabolism (Naguib FMN, el Kouni MH and Cha S, Biochem Pharmacol 38: 1471-1480, 1989). The effect of BBU on fluoropyrimidine catabolism in the liver was evaluated using the isolated perfused rat liver (IPRL). BBU infused at 0.35 μM over the course of 1 hr demonstrated no hepatotoxicity as measured by bile flow, O₂ uptake and lactate dehydrogenase leakage. The effect of BBU (0.35 μM) on the catabolism of FUra (10 μM) or FdUrd (10 μM) was quantitated by HPLC at 5- or 10-min intervals over a 1-hr period. BBU maximally inhibited FUra catabolism by approximately 83%. Further studies utilizing short-term (20 min) infusion of BBU prior to administration of FUra suggested that the inhibition of DPD was reversible. While FdUrd phosphorolysis was not affected, subsequent catabolism of FUra decreased by 70%. Studies on isolated hepatocytes indicated that the increased FUra level in perfusate resulted from inhibition of FUra catabolism and not from inhibition of FUra transport. The significant inhibition of FUra catabolism suggests that BBU may be useful in modulating regional chemotherapy by these fluoropyrimidines.