title: Pharmacokinetics of 5-carboranyl-2'-deoxyuridine in rats.
abstract: The pharmacokinetics of 5-carboranyl-2'-deoxyuridine (CDU) after intravenous administration of 25 mg/kg was investigated in rats. The uptake of CDU into brain was also examined. Concentrations of CDU in plasma, urine, and brain were measured by reverse phase HPLC. Plasma concentrations of CDU declined in a biexponential fashion with a terminal half-life of 1.26 +/- 0.28 h. The plasma protein binding of CDU was linear and the average fraction bound to plasma proteins was 0.95 +/- 0.02. The total clearance of CDU was 0.69 +/- 0.20 L/h/kg whereas clearance of unbound drug was much greater (15.33 +/- 4.44 L/h/kg). Thus, the total clearance of the drug is limited, in part, by the high degree of plasma protein binding, resulting in a moderate total clearance. No unchanged CDU was detected in urine. Furthermore, there was no trace of CDU glucuronide in urine samples. The steady-state volume of distribution of CDU was 0.70 +/- 0.23 L/kg. The brain:total plasma CDU concentration ratios determined in two rats were 0.47 and 0.36, while the brain:unbound plasma CDU concentration ratios were 10.26 and 7.87. The results of this study suggest that it is possible to achieve significant levels of CDU in brain. The high degree of plasma protein binding restricted extensive distribution of this lipophilic compound. The results of this study suggest further investigations of CDU as a neutron sensitizer for boron neutron capture therapy (BNCT) are warranted.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602.
authors.forename: V R
authors.initials: VR
authors.lastname: Jarugula
authors.forename: R F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: G
authors.initials: G
authors.lastname: Fulcrand
authors.forename: Y
authors.initials: Y
authors.lastname: el Kattan
authors.forename: D C
authors.initials: DC
authors.lastname: Liotta
authors.forename: F D
authors.initials: FD
authors.lastname: Boudinot
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001896:Boron Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001921:Brain / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D007262:Infusions, Intravenous; D008297:Male; D011485:Protein Binding; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001798:Blood Proteins; D001896:Boron Compounds; D011838:Radiation-Sensitizing Agents; C087057:5-carboranyl-2'-deoxyuridine; D003857:Deoxyuridine