title: Pharmacokinetics of DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f, in tumor-bearing mice.
abstract: 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.
authors.affiliation: Drug Metabolism and Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd. Tokyo, Japan. masub4p6@daiichipharm.co.jp
authors.forename: N
authors.initials: N
authors.lastname: Masubuchi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C452060:DE-310 cpd; D004337:Drug Carriers; C095887:exatecan; D002166:Camptothecin