Intravenous and oral pharmacokinetic study of BCX-1777, a novel purine nucleoside phosphorylase transition-state inhibitor.: In vivo effects on blood 2′-deoxyguanosine in primates

Administration of BCX-1777 to primates results in a rapid elevation of plasma T-deoxyguanosine (up to 0.4 mug/ml, 1.5 muM). Maximum 2 -deoxyguanosine C-max, 0.4 mug/ml, was achieved with the lowest IV dose of BCX-1777 and increasing the IV dose of BCX-1777 did not increase the T-deoxyguanosine C-max. However, plasma 2 -deoxyguanosine remained elevated longer as the dose of BCX-1777 increased. In contrast, increases in the oral dose of BCX-1777 did increase the plasma C-max. of 2'- deoxyguanosine. This was in spite of the observation that overall oral bioavailability of BCX-1777 was only 8.2%. This suggests that the BCX-1777 was absorbed slowly producing a sustained low concentration of BCX-1777, resulting in prolonged plasma concentrations of 2-deoxyguanosine. After IV dosing, the BCX-1777 was cleared relatively quickly and the plasma 2 deoxyguanosine tracked slightly behind the BCX-1777. IV administration of 5 mg/kg of BCX-1777 twice daily maintains the plasma 2'-deoxyguanosine concentrations at around 0.3 mug/ml (I. I muM). These data indicate that oral and IV administration of BCX-1777 induce a rapid rise in 2-deoxyguanosine and that oral dosing at 8.8 and 17.6 mg/kg are at least equivalent to 4.4 mg/kg IV in effecting the accumulation of 2 -deoxyguanosine. Finally, 2-deoxyguanosine plasma concentration was maintained longer in the three highest oral doses in comparison to all IV doses. (C) 2003 Elsevier Science B.V. All rights reserved.