Pharmacokinetics of DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f, in tumor-bearing mice.

To improve the distribution of the novel camptothecin analog DX-8951, DE-310, which is composed of DX-8951 covalently linked to a macromolecular carrier by a peptidyl (GGFG) spacer, was designed to exploit the Enhanced Permeability and Retention (EPR) effect. To compare the pharmacokinetics of a single dose of DE-310 with that of DX-8951f in Meth A tumor-bearing mice, the concentrations of conjugated DX-8951 (carrier-bound DX-8951), released DX-8951, and glycyl DX-8951 (G-DX-8951) were determined in plasma, liver, and tumor tissue. The concentrations of conjugated DX-8951 in tumor tissue were lower than those in plasma, with an AUC(0-inf) of 1/6 that of plasma; however, the AUC(0-inf) of released DX-8951 in tumor tissue was 30 times greater than that in plasma. The half-life (t1/2) of conjugated DX-8951, released DX-8951, and G-DX-8951 in plasma, liver, and tumor tissue were 2-3 days. In contrast, after administration of 14C-DX-8951f, the radioactivity in tumor tissue decreased in parallel with the decrease in plasma concentrations, with a t1/2(0.083-3 h) of 0.6 h. These data show that higher levels and longer retention of conjugated DX-8951 and released DX-8951 occur in tumor tissue after the administration of DE-310 to Meth A tumor-bearing mice. These results indicate that DE-310 improves the pharmacokinetic profileof DX-8951f, particularly, its ability to target tumor tissue.