Received for publication August 10, 2004.
Revised August 30, 2004.
Accepted for publication August 31, 2004.

Liver-Targeted Drug Delivery Using HepDirect^TM Prodrugs

Abstract

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 man-made 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^TM 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, a HepDirect prodrug of the nucleotide analogue adefovir (PMEA), and MB07133, 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 toxicologically most 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.

Key words: Acetaminophen, Cytarabine, Cytochrome P450 3A, Liver Targeting, PMEA, Prodrug

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