Fuse E, Tanii H, Takai K, Asanome K, Kurata N, Kobayashi H, Kuwabara T, Kobayashi S, Sugiyama Y
Drug Development Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Cancer Res. 1999 Mar 1;59(5):1054-60.
The large species difference in the pharmacokinetics/pharmacodynamics of 7-hydroxystaurosporine (UCN-01) can be partially explained by the high affinity binding of UCN-01 to human alpha1-acid glycoprotein (AGP) (Fuse et al, Cancer Res., 58: 3248-3253, 1998). To confirm whether its binding to human AGP actually changes the in vivo pharmacokinetics, we have studied the alteration in its pharmacokinetics after simultaneous administration of human AGP to rats: (a) the protein binding of UCN-01 was evaluated by chasing its dissociation from proteins using dextran-coated charcoal. The UCN-01 remaining 0.1 h after adding dextran-coated charcoal to human plasma or AGP was approximately 80%, although the values for other specimens, except monkey plasma (approximately 20%), were <1%, indicating that the dissociation from human AGP was specifically slower than from other proteins; and (b) the pharmacokinetics of UCN-01 simultaneously administered with human AGP has been determined. The plasma concentrations after i.v. administration of UCN-O1 with equimolar human AGP were much higher than those after administration of UCN-01 alone. The steady-state distribution volume and the systemic clearance were reduced to about 1/100 and 1/200, respectively. Human AGP thus reduced the distribution and elimination of UCN-01 substantially. On the other hand, dog AGP, which has a low binding affinity for UCN-01, did not change the pharmacokinetics of UCN-01 so much. Furthermore, human AGP markedly reduced the hepatic extraction ratio of UCN-01 from 0.510 to 0.0326. Also, human AGP (10 microM) completely inhibited the initial uptake of UCN-01 (1 microM) into isolated rat hepatocytes, whereas the uptake of UCN-01 was unchanged in the presence of human serum albumin (10 microM). In conclusion, the high degree of binding of UCN-01 to human AGP causes a reduction in the distribution and clearance, resulting in high plasma concentrations in humans.
7-羟基星孢菌素（UCN-01）药代动力学/药效学方面存在较大的物种差异，这可以部分归因于UCN-01与人α1-酸性糖蛋白（AGP）的高亲和力结合（Fuse等人，《癌症研究》，58: 3248 - 3253，1998）。为了证实其与人AGP的结合是否真的会改变体内药代动力学，我们研究了向大鼠同时给药人AGP后UCN-01药代动力学的变化：（a）通过使用葡聚糖包被的活性炭追踪UCN-01从蛋白质上的解离来评估其蛋白质结合情况。向人血浆或AGP中加入葡聚糖包被的活性炭0.1小时后，剩余的UCN-01约为80%，尽管除猴血浆（约20%）外的其他样本的值<1%，这表明从人AGP上的解离比从其他蛋白质上的解离特别慢；（b）已确定了与人类AGP同时给药时UCN-01的药代动力学。静脉注射等摩尔人AGP后，UCN-O1的血浆浓度远高于单独给药UCN-01后的浓度。稳态分布容积和全身清除率分别降至约1/100和1/200。因此，人AGP显著降低了UCN-01的分布和消除。另一方面，对UCN-01结合亲和力较低的犬AGP对UCN-01药代动力学的影响不大。此外，人AGP显著降低了UCN-01的肝脏提取率，从0.510降至0.0326。而且，人AGP（10微摩尔）完全抑制了UCN-01（1微摩尔）对分离的大鼠肝细胞的初始摄取，而在人血清白蛋白（10微摩尔）存在的情况下，UCN-01的摄取没有变化。总之，UCN-01与人AGP的高度结合导致分布和清除减少，从而使人体血浆浓度升高。
Zotero 插件