TARGETING OF NAPROXEN COVALENTLY-LINKED TO HSA TO SINUSOIDAL CELL-TYPES OF THE LIVER

The kinetic behaviour of a naproxen human serum albumin conjugate (Nap (23)-HSA) was investigated in rats and in isolated perfused rat livers (IPRL), as compared to its active metabolite naproxen-lysine (Nap-lys ine) and free naproxen. Through covalently linking the antiinflammator y drug naproxen to HSA, this drug can be selectively delivered to non parenchymal cells of the liver. Liver endothelial and Kupffer cells pl ay an important role in the pathogenesis of inflammatory liver disease s. Targeting naproxen to these cells might increase its efficacy and r educe the side effects. The altered kinetic properties of Nap(23)-HSA, after i.v. injection of 22 mg.kg(-1), as compared to an equimolar amo unt of the uncoupled drug, were demonstrated in vivo by a decrease in the steady state volume of distribution (41 +/- 5 vs. 134 +/- 19 ml.kg (-1)), a decrease in its clearance (0.48 +/- 0.05 vs. 0.63 +/- 0.1 ml. min(-1).kg(-1)), a shorter plasma half life (60 +/- 11 vs. 152 +/- 44 min) and a sustained biliary excretion. Liver targeting of Nap(23)-HSA was clearly demonstrated: drug content of the liver 180 min after inj ection was about 30 times higher for Nap(23)-HSA as compared to naprox en itself. The IPRL experiments showed that the V-max of hepatic remov al of the conjugate was 40 mu g.min(-1).g liver(-1). With doses below receptor saturation a rapid removal of the conjugate (t(1/2) = 6 min) from the perfusion medium was found. In conclusion, this study demonst rates the saturable uptake of Nap(23)-HSA and its lysosomal degradatio n in both in vivo and IPRL, experiments. Covalently linked naproxen is released as Nap-lysine. This active metabolite accumulates in Kupffer and endothelial cells in which it reaches therapeutic concentrations. Release from these cells leads to rapid uptake by hepatocytes and car rier mediated excretion into bile. Levels of Nap-lysine in bile and pl asma reflect the slowest step in its generation: the proteolytic relea se in endothelial and Kupffer cells.