Effect of chronic bile duct obstruction and LPS upon targeting of naproxen to the liver using naproxen-albumin conjugate

Naproxen covalently linked to human serum albumin (NAP-HSA) is efficiently targeted to endothelial and Kupffer cells of the liver and may offer a new therapeutic approach in the treatment of liver disease associated with inflammatory processes. In the present investigation we explored the pharmacokinetic behaviour of targeted and non-targeted naproxen as well as the pharmacokinetic properties of the active metabolite, Naproxen-lysine (Nap-lysine), in rats rendered fibrotic by bile duct ligation (BDL) for 4 weeks. Furthermore, we studied the effect of endotoxemia, experimentally induced by intravenous injection of 800 mu g/kg lipopolysaccaride (LPS) upon the pharmacokinetics of these agents in order to investigate the feasibility of targeting naproxen to nonparenchymal cells in the inflamed and fibrotic liver. Our studies demonstrate that liver disease altered the pharmacokinetic behaviour of the different naproxen compounds. Thus, initial plasma concentrations of NAP-HSA and naproxen were markedly lower in BDL rats accompanied by an increase of the volume of distribution during the terminal elimination phase(Vd(beta) BDL vs control 114 +/- 63 vs 50 +/- 7 and 202 +/- 24 vs 115 +/- 11 ml/kg for naproxen and NAP-HSA, respectively). After injection of LPS, no significant change in the pharmacokinetics of NAP-HSA was found whereas the naproxen treated control animals showed an increase in the terminal volume of distribution (176 +/- 34 vs 115 +/- 11 ml/kg) as well as an elevation of the plasma half-life (171 +/- 27 vs 116 +/- 14 min). The feasibility of targeting naproxen to the chronically diseased liver could be clearly demonstrated: 15 min after administration of the conjugate 46% and 55% of the administered dose was found in the liver of CTR and BDL rats, whereas after injection of free naproxen only 5% and 12% of the dose was detected in liver tissue, respectively. We conclude that targeting albumin-linked naproxen to non-parenchymal cells in the liver is still feasible under the pathological conditions induced in the present study. Liver fibrosis induced significant alterations in the pharmacokinetic behaviour of the studied compounds.