title: Pharmacokinetics and bioavailability of 5-ethyl-2'-deoxyuridine and its novel (5R,6R)-5-bromo-6-ethoxy-5,6-dihydro prodrugs in mice.
abstract: The pharmacokinetics and oral (po) bioavailability of 5-ethyl-2'-deoxyuridine (EDU) and its novel 5,6-dihydro prodrugs (+)-trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-2'-deoxyuridine (BEEDU) and (+)-trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-5'-O-valeryl-2'- deoxyuridine (VBEEDU) were determined in male Balb/C mice following intravenous and no administration of a 0.4 mmol/kg dose. EDU was eliminated from blood with a half-life of 35.2 +/- 4.2 min. The mean residence time (MRT) and the area under the blood vs. time curve (AUC) for EDU after iv injection were 45.1 +/- 11.7 min and 1.7 +/- 0.2 mumol.g-1.min, respectively. EDU showed a 49% bioavailability in male.Balb/C mice. The pharmacokinetic parameters and bioavailability of EDU were improved significantly upon administration of the 5,6-dihydro prodrugs BEEDU or VBEEDU. The AUC of EDU after a 0.4 mmol/kg iv dose of BEEDU was 2.1 +/- 0.3 mumol.g-1.min, which is substantially higher than that after iv injection of EDU. The half-life and MRT of EDU were increased to 251.9 +/- 30.2 min and 352.0 +/- 91.5 min, respectively, after injection of BEEDU. The po bioavailability of EDU, after administration of BEEDU, was increased almost 2-fold (81%), compared with that of EDU (49%). The AUC of EDU after iv injection of VBEEDU was 1.8 +/- 0.2 mumol.g-1.min. The half-life and MRT of EDU, the active metabolite of VBEEDU, were 106.0 +/- 23.2 min and 157.0 +/- 40.8 min, which are substantially higher than those for EDU after administration of EDU.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Cheraghali
authors.forename: R
authors.initials: R
authors.lastname: Kumar
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001973:Bromodeoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003857:Deoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: C093379:5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-2'-deoxyuridine; C093380:5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-5'-O-valeryl-2'-deoxyuridine; D000998:Antiviral Agents; D011355:Prodrugs; C022811:edoxudin; D001973:Bromodeoxyuridine; D003857:Deoxyuridine