title: Pharmacokinetics of 3'-O-retinoyl-5-fluoro-2'-deoxyuridine (RFUdR), a dual acting mutually masking prodrug, and its metabolites in tumor bearing mice.
abstract: 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/L.min) was estimated to be about 4- fold higher than its AUC in the plasma (809 ± 241 μmol/L.min). 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.
authors.affiliation: Div. Nucl. Med., Cross Cancer Institute, Edmonton, AB, Canada T6G 1Z2.. leonard.wiebe@ualberta.ca.
authors.forename: Zuping
authors.initials: Z
authors.lastname: Xia
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Wiebe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D005260:Female; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D005467:Floxuridine