Pharmacokinetics of 3’-O-Retinoyl-5-fluoro-2’-deoxyuridine (RFUdR), a Dual Acting Mutually Masking Prodrug, and Its Metabolites in Tumor Bearing Mice

Author(s): Zuping Xia, Edward E. Knaus, Leonard I. Wiebe

Journal Name: Current Drug Delivery

Volume 10 , Issue 5 , 2013

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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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Article Details

Year: 2013
Published on: 04 September, 2013
Page: [557 - 563]
Pages: 7
DOI: 10.2174/15672018113109990038
Price: $65

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