Pharmacokinetic studies of 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyl-oxybut-1-yl)purine, an oral prodrug for the antiviral agent penciclovir

2-Amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)-purine (SK1899) was tested as an oral prodrug for penciclovir. SK1899 was administered ora lly to rats and dogs at doses up to 2 and 0.68 mmol/kg, respectively. SK189 9 was well absorbed, and the major metabolites detected in plasma and urine were penciclovir, the active antiviral compound, and 6-deoxypenciclovir (M 4) in both species. In rats, SK1899 was rapidly and extensively metabolized to penciclovir, which reached the peak plasma concentration (C-max) of 39. 5 muM at 0.5 h after 0.2-mmol/kg dosing, The area under the plasma concentr ation-time curve (AUC) for penciclovir was 57.5 muM . h, After an oral dose of 0.034 mmol/kg to dogs, extensive conversion of SK1899 to penciclovir al so occurred with slower rate of formation of penciclovir from M4 than in ra ts. The mean C-max and AUC for penciclovir were 4.5 muM at 2.7 h and 28.2 m uM . h, respectively, The 0- to 24-h urinary recovery of penciclovir repres ented 36.1 and 36.3% of dose to rats and dogs, respectively. Radioactivity was found in fetuses following an oral administration of [C-14]SK1899 to pr egnant rats, but no significant accumulation was observed. Although substan tial milk transfer of [C-14]SK1899 occurred in rats, the radioactivity in m ilk was rapidly cleared, The values of C-max, AUC, and urinary recovery of penciclovir after dosing with SK1899 to rats and dogs were similar or sligh tly higher than those from famciclovir, These data indicate that introducti on of an isopropoxy carbonate group into one of the two hydroxyl groups of M4 did not significantly alter the oral bioavailability of penciclovir comp ared with famciclovir.