Effect of chronic bile duct obstruction and LPS upon targeting of naproxento 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 infl ammatory processes. In the present investigation we explored the pharmacoki netic behaviour of targeted and non-targeted naproxen as well as the pharma cokinetic properties of the active metabolite, Naproxen-lysine (Nap-lysine) , in rats rendered fibrotic by bile duct ligation (BDL) for 4 weeks. Furthe rmore, we studied the effect of endotoxemia, experimentally induced by intr avenous injection of 800 mu g/kg lipopolysaccaride (LPS) upon the pharmacok inetics of these agents in order to investigate the feasibility of targetin g naproxen to nonparenchymal cells in the inflamed and fibrotic liver. Our studies demonstrate that liver disease altered the pharmacokinetic behaviou r of the different naproxen compounds. Thus, initial plasma concentrations of NAP-HSA and naproxen were markedly lower in BDL rats accompanied by an i ncrease 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 +/- 1 1 ml/kg for naproxen and NAP-HSA, respectively). After injection of LPS, no significant change in the pharmacokinetics of NAP-HSA was found whereas th e naproxen treated control animals showed an increase in the terminal volum e 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 demon strated: 15 min after administration of the conjugate 46% and 55% of the ad ministered dose was found in the liver of CTR and BDL rats, whereas after i njection 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 i n the present study. Liver fibrosis induced significant alterations in the pharmacokinetic behaviour of the studied compounds.