Modulation of the pharmacokinetics of endogenous plasma uridine by 5-(phenylthio) acyclouridine, a uridine phosphorylase inhibitor: implications for chemotherapy

Purpose: The purpose of this investigation was to evaluate the ability of o ral PTAU, 5-(phenylthio)acyclouridine, to increase the concentration of end ogenous plasma uridine. PTAU is a new potent and specific inhibitor of urid ine 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 involv ed in uridine catabolism. Methods: PTAU was administered to mice orally and parenterally. The plasma levels of PTAU as well as those of uridine and it s catabolite uracil were measured by HPLC, and pharmacokinetic analysis was performed. Results: PTAU was fully adsorbed after oral administration (ove r 100% oral bioavailability) and no PTAU metabolites were detected. PTAU ad ministered orally had no apparent toxicity at doses up to 120 mg/kg per day for 5 days. Parenteral administration of PTAU at 30, 45 and 60 mg/kg incre ased the concentration of endogenous plasma uridine (1.8 +/- 0.2 muM) by ap proximately six-, seven-, and nine-fold, respectively. Plasma uridine conce ntration remained higher than control values until 8 h after PTAU administr ation. Similar results were obtained following oral administration of PTAU. The baseline concentrations of endogenous plasma uridine were increased by approximately six-, seven- and ten-fold by oral administration of PTAU at 30, 45 and 60 mg/kg, respectively, and remained higher than the controls un til 8 h after PTAU administration. PTAU did not alter the concentration of endogenous plasma uracil. Conclusion: The effectiveness of the PTAU in elev ating and sustaining high plasma uridine concentrations may be useful in re scuing or protecting the host from toxicities of various chemotherapeutic p yrimidine analogues as well as in the management of medical disorders that respond to the administration of uridine.