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 2′-deoxyguanosine (up to 0.4 μg/ml, 1.5 μM). Maximum 2′-deoxyguanosine Cmax, 0.4 μg/ml, was achieved with the lowest IV dose of BCX-1777 and increasing the IV dose of BCX-1777 did not increase the 2′-deoxyguanosine Cmax. 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 Cmax 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 μg/ml (1.1 μM). 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.