Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: implications for uridine rescue regimens in chemotherapy.

Abstract

The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the oral bioavailability of uridine. PTAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. 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. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). PTAU was administered orally to mice alone or with uridine. The plasma levels of PTAU as well as those of uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. Co-administration of PTAU with uridine elevated the concentration of plasma uridine in a dose-dependent manner over that resulting from the administration of the same dose of uridine alone, and reduced the clearance of uridine as well as the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Coadministration of PTAU at 30, 45 and 60 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9- and 9.9-fold, respectively, and reduced the AUC of plasma uracil (1227.8 micromol x h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45 and 60 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.8-, 2.6- and 2.8-fold, and that of 660 mg/kg uridine by 2.2-, 2.6- and 3.2-fold, respectively. The effectiveness of PTAU in improving the oral bioavailability of uridine could be useful in the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by administration of uridine.