PHARMACOKINETICS OF 5-CARBORANYL-2'-DEOXYURIDINE IN RATS

The pharmacokinetics of 5-carboranyl-2'-deoxyuridine (CDU) after intra venous 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 concentr ations 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 to tal clearance of the drug is limited, in part, by the high degree of p lasma protein binding, resulting in a moderate total clearance. No unc hanged CDU was detected in urine. Furthermore, there was no trace of C DU glucuronide in urine samples. The steady-state volume of distributi on of CDU was 0.70 +/- 0.23 L/kg. The brain:total plasma CDU concentra tion 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 resu lts of this study suggest that it is possible to achieve significant l evels of CDU in brain. The high degree of plasma protein binding restr icted extensive distribution of this lipophilic compound. The results of this study suggest further investigations of CDU as a neutron sensi tizer for boron neutron capture therapy (BNCT) are warranted.