RT Journal Article
SR Electronic
T1 Liver-Targeted Drug Delivery Using HepDirect Prodrugs
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 554
OP 560
DO 10.1124/jpet.104.075903
VO 312
IS 2
A1 Mark D. Erion
A1 Paul D. van Poelje
A1 Deidre A. MacKenna
A1 Timothy J. Colby
A1 Annika C. Montag
A1 James M. Fujitaki
A1 David L. Linemeyer
A1 David A. Bullough
YR 2005
UL http://jpet.aspetjournals.org/content/312/2/554.abstract
AB Targeting drugs to specific organs, tissues, or cells is an attractive strategy for enhancing drug efficacy and reducing side effects. Drug carriers such as antibodies, natural and manmade polymers, and labeled liposomes are capable of targeting drugs to blood vessels of individual tissues but often fail to deliver drugs to extravascular sites. An alternative strategy is to use low molecular weight prodrugs that distribute throughout the body but cleave intracellularly to the active drug by an organ-specific enzyme. Here we show that a series of phosphate and phosphonate prodrugs, called HepDirect prodrugs, results in liver-targeted drug delivery following a cytochrome P450-catalyzed oxidative cleavage reaction inside hepatocytes. Liver targeting was demonstrated in rodents for MB06866 [(2R,4S)-9-[2-[4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methoxyethyl]adenine (remofovir)], a Hep-Direct prodrug of the nucleotide analog adefovir (PMEA), and MB07133 [(2R,4S)-4-amino-1-[5-O-[2-oxo-4-(4-pyridyl)-1,3,2-dioxaphosphorinan-2-yl]-β-d-arabinofuranosyl]-2(1H)-pyrimidinone], a HepDirect prodrug of cytarabine (araC) 5′-monophosphate. Liver targeting led to higher levels of the biologically active form of PMEA and araC in the liver and to lower levels in the most toxicologically sensitive organs. Liver targeting also confined production of the prodrug byproduct, an aryl vinyl ketone, to hepatocytes. Glutathione within the hepatocytes rapidly reacted with the byproduct to form a glutathione conjugate. No byproduct-related toxicity was observed in hepatocytes or animals treated with HepDirect prodrugs. A 5-day safety study in mice demonstrated the toxicological benefits of liver targeting. These findings suggest that HepDirect prodrugs represent a potential strategy for targeting drugs to the liver and achieving more effective therapies against chronic liver diseases such as hepatitis B, hepatitis C, and hepatocellular carcinoma.