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

Citation
On. Al Safarjalani et al., Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio) acyclouridine, a uridine phosphorylase inhibitor: implications for uridine rescue regimens in chemotherapy, CANC CHEMOT, 48(5), 2001, pp. 389-397
Citations number
77
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
5
Year of publication
2001
Pages
389 - 397
Database
ISI
SICI code
0344-5704(200111)48:5<389:EOTBOO>2.0.ZU;2-X
Abstract
Purpose: The purpose of this investigation was to evaluate the effectivenes s of oral 5-(phenylthio)acyclouridine (PTAU) in improving the oral bioavail ability of uridine. PTAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine cat abolism. This compound was designed as a lipophilic inhibitor in order to f acilitate its access to the liver and intestine, the main organs involved i n uridine catabolism. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). Methods: PTAU was adminis tered orally to mice alone or with uridine. The plasma levels of PTAU as we ll as those of uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. Results: Coadministration of PT AU with uridine elevated the concentration of plasma uridine in a dose-depe ndent manner over that resulting from the administration of the same dose o f uridine alone, and reduced the clearance of uridine as well as the peak p lasma concentration (C-max) and area under the curve (AUC) of plasma uracil . Coadministration of PTAU at 30. 45 and 60 mg/kg improved the low oral bio availability (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 mu mo l.h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were obser ved 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. Conclusion: The effectiveness of PTAU in improving the oral bioavailability of uridine could be useful in the rescue or prote ction from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by adm inistration of uridine.