Modulation of plasma uridine concentration by 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase: relevance to chemotherapy

Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acyclouridine (PSAU) in increasing endogenous plas ma uridine concentration as well as its ability to improve the bioavailabil ity of oral uridine. PSAU is a new potent and specific inhibitor of uridine phosphorylase (Urd-Pase, EC 2.4.2.3), the enzyme responsible for uridine c atabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. Methods: Oral PSAU was administered orally to mice alone or with uridine. The plasma levels of PSAU as well as uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. Results: PSAU has an oral bioavail ability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg in creased baseline concentration of endogenous plasma uridine (2.6 +/- 0.7 mu M) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold hi gher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of P SAU with uridine elevated the concentration of plasma uridine over that res ulting from the administration of either alone, and reduced the peak plasma concentration (C-max) and area under the curve (AUC) of plasma uracil, Co- administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavaila bility of oral uridine (7.7%) administered at 1320 mg/kg by 4.8- and 4.2-fo ld, respectively, and reduced the AUC of plasma uracil from 1421 to 787 mu mol/h . 1 and 273 mu mol/h . 1, respectively. Similar results were observed when PSAU was co-administered with lower doses of uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg uridine by 6.4- and 9.0-f old, respectively. However, the reduction in the AUC values of plasma uraci l was less dramatic than that seen when the high dose of 1320 mg/kg uridine was used. Conclusion: The effectiveness of the PSAU plus uridine combinati on in elevating and sustaining high plasma uridine concentration may be use ful to rescue or protect from host toxicity of various chemotherapeutic pyr imidine analogs as well as in the management of medical disorders that are remedied by administration of uridine.