3’-O-Retinoyl-5-fluoro-2’-deoxyuridine (RFUdR) is a putative dual-acting, mutually-masking (DAMM) prodrug
for the treatment of cancer. As part of the proof of principle for the DAMM concept, the concentrations of RFUdR
and its post-hydrolysis active metabolites, 5-fluoro-2’-deoxyuridine (FUdR) and all-trans-retinoic acid (RA), were determined
in plasma and selected tissues following either bolus intravenous (i.v.; 12.5 μmol/kg) or oral (p.o.; 13.7 μmol/kg)
doses of RFUdR to mice bearing EMT6 murine mammary tumors. The concentrations of RFUdR and its primary metabolites
were measured by high-performance liquid chromatography. A three compartment model provided the best fit for
plasma RFUdR after an i.v. bolus, whereas FUdR and RA data were best fit by a one compartment model. The terminal
half-life of RFUdR in plasma was 9 hours. The AUC of RFUdR in tumor (3400 μmol/Lmin) was estimated to be about 4-
fold higher than its AUC in the plasma (809±241 μmol/Lmin). A short-duration, saturated elimination phase for RFUdR
was observed in both liver and kidney following an i.v. bolus. Neither unchanged RFUdR nor RA was detected in urine.
The high bioavailability (~90%) following oral dosing with RFUdR indicates that this DAMM prodrug may be suitable
for oral dosing to deliver FUdR and RA for cancer chemotherapy.
Keywords: Pharmacokinetics, dual-acting, mutually-masking prodrug (DAMM), 3’-O-retinoyl-5-fluoro-2’-deoxyuridine
(RFUdR), 5-fluoro-2’-deoxyuridine (FUdR), all-trans-retinoic acid (RA).
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Published on: 31 August, 2013
Page: [557 - 563]