ENHANCED ORAL ABSORPTION AND ANTIVIRAL ACTIVITY OF 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHO-ACYCLOVIR AND RELATED-COMPOUNDS IN HEPATITIS-B VIRUS-INFECTION, IN-VITRO

Acyclovir (ACV) triphosphate and azidothymidine (AZT) triphosphate inh ibit the DNA polymerase of human hepatitis B virus (HBV) by 50% at sub micromolar concentrations, but no effects of ACV or AZT treatment have been noted on the clinical manifestations of hepatitis B. We synthesi zed 1-O-actadecyl-sn-glycero- 3-phospho-acyclovir (ODG-P-ACV), 1-O-hex adecylpropanediol-3-phospho-acyclovir (HDP P-ACV), and 1-O-octadecyl-s n-glycero-3-phospho-azidothymidine (ODG-P-AZT), and evaluated their an tiviral activity in human hepatoma cells that constitutively produce H BV (2.2.15 cells). ACV and AZT up to 100 mu M caused only slight inhib ition of HBV replication in 2.2.15 cells. However, HDP-P-ACV and ODG-P -ACV inhibited viral replication by 50% at 0.5 and 6.8 mu M, respectiv ely. ODG-P-AZT also showed increased antiviral activity, with a 50% re duction in HBV replication at 2.1 mu M. Based on the EC50, HDP-P-ACV, ODG-P-ACV, and ODG-P-AZT were > 200, > 14.7, and > 48 times more activ e than their free nucleosides in reducing HBV replication in 2.2.15 ce lls. To evaluate the biochemical basis for the increased antiviral act ivity, we studied the uptake and metabolism of 1-O-octadecyl-sn-glycer o-3-phospho-[H-3]acyclovir (ODG-P-[H-3]ACV) in HepG2 cells. Cellular u ptake of ODG-P-[H-3]ACV was found to be substantially greater than tha t of [H-3]ACV, and cellular Levels of ACV-mono-, -di-, and -triphospha te were much higher with ODG-P-ACV. ODG-P-[H-3]ACV was well absorbed o rally. Based on urinary recovery of tritium after oral or parenteral a dministration of the radiolabeled compounds, oral absorption of ODG-P- ACV in mice was 100% versus 37% for ACV. ODG-P-ACV plasma area under t he curve was more than 7-fold greater than that of ACV. Lipid prodrugs of this type may be useful orally in treating viral diseases. (C) 199 7 Elsevier Science Inc.