Oral 1-O-octadecyl-2-O-benzyl-sn-glycero-3-cidofovir targets the lung and is effective against a lethal respiratory challenge with ectromelia virus in mice.
Hexadecyloxypropyl-cidofovir (HDP-CDV) has been shown to be orally active against lethal infection with orthopoxviruses including, mousepox, cowpox, vaccinia and rabbitpox. The alkoxyalkyl group provides oral absorption and reduces greatly the amount of drug reaching the kidney, the site of CDV's dose limiting toxicity. However, the amount of HDP-CDV detected in lung, an important site of early poxvirus replication, is low and the reduction of viral titers in surviving animals is reduced moderately compared with the liver where poxvirus titers are virtually undetectable. We synthesized a novel glycerol ester of CDV, 1-O-octadecyl-2-O-benzyl-sn-glycero-3-CDV (ODBG-CDV), and compared its oral pharmacokinetics with that of HDP-CDV. Surprisingly, ODBG-CDV levels in lung are much higher and liver levels are reduced, suggesting that the compound is transported in small intestinal lymph instead the portal vein. ODBG-CDV has excellent in vitro activity in cells infected with ectromelia virus (ECTV). In mice infected with a lethal aerosol or intranasal challenge of ECTV, HDP-CDV and ODBG-CDV are equally effective in preventing death from disease. Other drugs esterified to 1-O-octadecyl-2-O-benzyl-sn-glycerol or 1-O-octadecyl-2-O-benzyl-sn-glycerol-3-phosphate may provide lung targeting for treatment of microbial or neoplastic diseases while reducing first pass removal by the liver during oral absorption.
Hostetler
Karl Y
KY
Department of Medicine, Division of Infectious Disease, University of California, San Diego, La Jolla, CA 92093-0676, United States. khostetl@ucsd.edu
Beadle
James R
JR
Trahan
Julissa
J
Aldern
Kathy A
KA
Owens
Gelita
G
Schriewer
Jill
J
Melman
Lora
L
Buller
R Mark
RM
D000284:Administration, Oral; D000818:Animals; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004481:Ectromelia virus / Q000187:drug effects*; D004482:Ectromelia, Infectious / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D005260:Female; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D051379:Mice; D063065:Organophosphonates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology
C521192:1-O-octadecyl-2-O-benzyl-sn-glycero-3-cidofovir; D063065:Organophosphonates; C493733:hexadecyloxypropyl-cyclic cidofovir; D003596:Cytosine; D000077404:Cidofovir