Enhanced accumulation of ribavirin and its metabolites in liver versus erythrocytes in mice administered with the liver targeted drug.
BACKGROUND
Ribavirin increases the efficacy of alpha-interferon in chronic hepatitis C, but accumulates in erythrocytes causing haemolysis.


OBJECTIVE
To reduce this side effect we conjugated ribavirin with lactosaminated poly-L-lysine.


METHODS
In mice administered with the same dose of free or conjugated [3H]ribavirin we determined the levels of radioactivity in liver and erythrocytes and measured the hepatic concentrations of ribavirin triphosphate. Moreover, we determined the doses of free and conjugated ribavirin producing a 50% reduction in the virus titre (ED50) in liver of mice infected with murine hepatitis virus.


RESULTS
In mice treated with the conjugate, the ratio dpm in liver/dpm in erythrocytes was 2.2- or 4.7-fold higher than in animals administered with the free drug given intramuscularly or orally, respectively. The concentration of [3H]ribavirin triphosphate was found to be 2-fold higher in mice injected with the conjugated drug than in animals orally treated with free ribavirin. In murine hepatitis virus infected mice, the ED50 was 27.4 micrograms/g for conjugated ribavirin and 47.2 micrograms/g for the free drug.


CONCLUSIONS
These results support the possibility that conjugated ribavirin may produce the same pharmacological activity in liver as the free drug but with a reduced haemolysis.
Di Stefano
G
G
Department of Experimental Pathology, University of Bologna, Italy.
Bignamini
A
A
Busi
C
C
Colonna
F P
FP
Fiume
L
L
D000606:Amino Sugars; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D006517:Murine hepatitis virus / Q000187:drug effects; D011107:Polylysine; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014316:Tritium
D000606:Amino Sugars; D000998:Antiviral Agents; D014316:Tritium; C032233:lactosamine; D011107:Polylysine; D012254:Ribavirin