Liver targeting of nucleoside analogues coupled to galactosyl terminating macromolecules: a new approach to the treatment of a chronic viral hepatitis.

In order to reduce the extrahepatic side effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with a receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The majority of experiments referred to in this paper were performed employing a conjugate of lactosaminated human albumin with adenine arabinoside monophosphate (ara-AMP), a phosphorylated nucleoside analogue active against hepatitis B virus. This conjugate administered for 28 days to patients with chronic hepatitis B exerted the same antiviral activity as that of the free drug without producing any clinical side effects, including the severe neurotoxicity caused by free ara-AMP. This result demonstrates the validity of the liver targeting approach which enhances the therapeutic possibilities of nucleoside analogues. Coupling to galactosyl terminating carriers may be a way of obtaining higher drug concentrations within hepatocytes and permitting the use of nucleoside analogues, the administration of which would otherwise be impossible due to extrahepatic toxicity.