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