Disposition of cosalane, a novel anti-HIV agent, in isolated perfused rat livers

Cosalane is a potent inhibitor of HIV replication with a broad range of act ivity. In this study, the hepatic disposition of cosalane was investigated with a noncirculating isolated perfused rat liver technique, When 6 mu M co salane was infused into livers from untreated rats, the drug was highly ext racted by the liver (only 2.5% of influent cosalane concentration appeared in the effluent perfusate). Pretreatment of rats with various inducers of c ytochrome P-450 before perfusion neither altered the effluent cosalane conc entration nor resulted in the appearance of detectable metabolites in the e ffluent perfusate or liver homogenates. Hepatic uptake of cosalane was negl igible when the drug was infused in the presence of BSA, and infusion of al bumin after cosalane resulted in a significant displacement: of the drug in to the effluent perfusate, Furthermore, permeabilization of perfused livers with digitonin significantly diminished effluent cosalane concentration wh ile enhancing cosalane uptake by the liver. Based on our data, it appears t hat a significant proportion of cosalane does not penetrate the hepatocyte membrane and may accumulate in the lipid bilayer of the cell membrane. This finding supports the proposed mechanism explaining the antiviral effect of cosalane which stipulates that this compound appears to imbed perpendicula rly in the lipid bilayer of the cell membrane and the viral envelope. Also, cosalane does not seem to be metabolized by the liver as evidenced by the lack of detectable metabolites in the effluent perfusate, liver homogenates , and liver microsomal incubations.