title: 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.
abstract: Administration of BCX-1777 to primates results in a rapid elevation of plasma 2'-deoxyguanosine (up to 0.4 microg/ml, 1.5 microM). Maximum 2'-deoxyguanosine C(max), 0.4 microg/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 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 microg/ml (1.1 microM). 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.
authors.affiliation: BioCryst Pharmaceuticals, Inc, 2190 Parkway Lake Drive, Birmingham, AL 35244, USA. jkilpatrick@biocryst.com
authors.forename: J Michael
authors.initials: JM
authors.lastname: Kilpatrick
authors.forename: Philip E
authors.initials: PE
authors.lastname: Morris
authors.forename: David G
authors.initials: DG
authors.lastname: Serota
authors.forename: Deborah
authors.initials: D
authors.lastname: Phillips
authors.forename: D Ray
authors.initials: DR
authors.lastname: Moore
authors.forename: J Claude
authors.initials: JC
authors.lastname: Bennett
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D003849:Deoxyguanosine / Q000097:blood*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D007275:Injections, Intravenous; D007288:Inosine / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; C113101:forodesine; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine