Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Eur J Pharm Biopharm. 2010 Jun;75(2):90-5. doi: 10.1016/j.ejpb.2010.03.010. Epub 2010 Mar 21.
The aim of this study was to assess the potential of polymeric micelles to solubilize valspodar and modify its pharmacokinetics following intravenous and oral administration in rat. Drug-loaded methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) micellar solutions were prepared and administered either intravenously or orally to healthy Sprague-Dawley rats. Plasma pharmacokinetic parameters of valspodar in its polymeric micellar formulation were compared to its clinical formulation, which uses Cremophor EL and ethanol as solubilizing agents. High loading level was achieved for valspodar in PEO-b-PCL leading to an aqueous solubility of 2.8 mg/mL. Following i.v. administration (5 mg/kg), valspodar in the PEO-b-PCL micelles provided significantly higher (approximately 77%) plasma AUC compared to the Cremophor EL formulation. The PEO-b-PCL micelles also significantly decreased the volume of distribution (Vd(ss)) and clearance (CL) of valspodar by nearly 49% and 34%, respectively. After oral administration (10 mg/kg), the average C(max) were similar for both formulations and were both reached at approximately 2 h. The plasma unbound fraction of valspodar in the polymeric micellar formulation was significantly lower than control (8.27% versus 14.85%). Our results show that PEO-b-PCL micelles can efficiently solubilize valspodar and favorably modify its pharmacokinetic profile in rat after i.v. administration by decreasing the CL and Vd.
本研究旨在评估聚合物胶束增溶缬更昔洛韦并改变其在大鼠体内静脉和口服给药后的药代动力学特性。载药甲氧基聚（乙二醇）-b-聚（ε-己内酯）（PEO-b-PCL）胶束溶液通过静脉内或口服途径给予健康 Sprague-Dawley 大鼠。比较缬更昔洛韦在其聚合物胶束制剂中的药代动力学参数与其临床制剂，后者使用聚氧乙烯蓖麻油和乙醇作为增溶剂。PEO-b-PCL 中缬更昔洛韦的载药量高，导致其水溶解度为 2.8mg/mL。静脉内给药（5mg/kg）后，PEO-b-PCL 胶束中的缬更昔洛韦提供的血浆 AUC 明显高于聚氧乙烯蓖麻油制剂（约 77%）。PEO-b-PCL 胶束还使缬更昔洛韦的分布容积（Vd(ss)）和清除率（CL）分别显著降低近 49%和 34%。口服给药（10mg/kg）后，两种制剂的平均 Cmax 相似，均在大约 2 小时达到。聚合物胶束制剂中缬更昔洛韦的血浆未结合分数明显低于对照（8.27%对 14.85%）。我们的结果表明，PEO-b-PCL 胶束可有效增溶缬更昔洛韦，并通过降低 CL 和 Vd ，在大鼠体内静脉给药后显著改变其药代动力学特征。
