Inducing a change in the pharmacokinetics and biodistribution of poly-L-lysine in rats by complexation with heparin.

The aim of our study was to induce changes in the plasma elimination half-life (t(1/2)(elim)), rate and extent of urinary excretion, and biodistribution of a model macromolecule, poly-L-lysine, in rats following complexation with heparin. Male Sprague-Dawley rats were dosed intravenously with either unfractionated [(3)H]heparin, FITC-labelled poly-L-lysine, or an [(3)H]heparin:FITC-labelled poly-L-lysine complex. Serum and blood concentration vs time and urinary excretion profiles were determined as well as the resulting patterns of biodistribution to liver, spleen, kidney, and muscle tissue. While the mean values for the total body clearance of poly-L-lysine and the complex were not significantly different, the volume of distribution and the half-life associated with elimination from the serum were increased greater than 2-fold for the complex compared with free poly-L-lysine. The rate and extent of elimination in the urine followed the relative rank order; heparin > poly-L-lysine> heparin:poly-L-lysine complex. Thirty minutes following intravenous administration, there was significantly more tissue deposition/uptake of the complex in the liver, kidney, and muscle, but not the spleen, when compared with poly-L-lysine administered alone. Complexation of heparin to poly-L-lysine effectively increased the fraction of an administered dose of poly-L-lysine that was deposited in liver, kidney, and muscle tissue. Due to the macromolecular complex being nontoxic and uncharged, potentially it might serve as a suitable carrier for both conventional and peptidic drugs to increase drug distribution to liver, kidney, or muscle tissue.

An antibody to IP-10 is a potent antagonist of cell migration in vitro and in vivo and does not affect disease in several animal models of inflammation.

IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC(50) of approximately 4 nM. The 20A9 mAb was completely absorbed in vivo and had dose proportional pharmacokinetic exposure with a serum half life of 2.4-6 days. The 20A9 mAb inhibited IP-10 mediated T-cell recruitment to the airways, indicating that it is effective in vivo. However, administration of the 20A9 mAb had no significant effect on disease in mouse models of delayed type hypersensitivity, collagen induced arthritis, cardiac allograft transplantation tolerance, EAE or CD4+ CD45RBHi T-cell transfer-induced IBD. These data suggest that the 20A9 mAb can antagonize IP-10 mediated chemotaxis in vitro and in vivo and that this is insufficient to cause a therapeutic benefit in multiple mouse models of inflammatory disease.