Masubuchi N
Drug Metabolism and Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd. Tokyo, Japan.
Pharmazie. 2004 May;59(5):374-7.
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.
为改善新型喜树碱类似物DX - 8951的分布，设计了DE - 310，它由DX - 8951通过肽基（GGFG）间隔基与大分子载体共价连接而成，旨在利用增强的渗透滞留（EPR）效应。为比较单剂量DE - 310与DX - 8951f在荷Meth A肿瘤小鼠体内的药代动力学，测定了血浆、肝脏和肿瘤组织中共轭DX - 8951（载体结合的DX - 8951）、释放的DX - 8951和甘氨酰DX - 8951（G - DX - 8951）的浓度。肿瘤组织中共轭DX - 8951的浓度低于血浆中的浓度，其AUC(0 - inf)为血浆的1/6；然而，肿瘤组织中释放的DX - 8951的AUC(0 - inf)比血浆中的大30倍。血浆、肝脏和肿瘤组织中共轭DX - 8951、释放的DX - 8951和G - DX - 8951的半衰期（t1/2）为2 - 3天。相比之下，给予14C - DX - 8951f后，肿瘤组织中的放射性与血浆浓度的降低平行下降，t1/2(0.083 - 3小时)为0.6小时。这些数据表明，给荷Meth A肿瘤小鼠施用DE - 310后，肿瘤组织中出现更高水平和更长时间滞留的共轭DX - 8951和释放的DX - 8951。这些结果表明，DE - 310改善了DX - 8951f的药代动力学特征，特别是其靶向肿瘤组织的能力。
