Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112.
Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112.
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DOI：
10.2147/ijn.s79734
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发表时间：
2015
影响因子：
8
通讯作者：
Wu B
中科院分区：
文献类型：
--
作者：
Dong D;Wang X;Wang H;Zhang X;Wang Y;Wu B
SNX-2112是一种很有前途的抗癌药物，但在水和油中的溶解度都很差。在本文报道的研究中，我们旨在开发SNX-2112的纳米晶体配方，并测定所制备的纳米晶体的药代动力学行为。采用湿介质研磨技术制备了SNX-2112纳米晶，并对其粒度、差示扫描量热法、药物释放等进行了表征。采用基于生理的药代动力学（PBPK）模型来评估给药共溶剂或纳米晶体后药物在大鼠体内的处置。优化后的SNX-2112纳米晶体尺寸为203 nm， zeta电位为- 11.6 mV（稳定剂为poloxam188）。此外，纳米晶体显示出与对照（药物共溶剂）相当的释放特征。此外，结合颗粒摄取（进入肝脏和脾脏）和体内药物释放参数的大鼠PBPK模型与给药纳米晶体后的实验数据很好地拟合。结果表明，纳米晶体在体内快速释放药物分子，这解释了它们的助溶剂样药代动力学行为。由于颗粒摄取，药物在肝脏和脾脏的蓄积在初始时间点（1小时内）是显著的。对于难溶性药物SNX-2112的全身递送，纳米晶体应该是一个很好的选择。此外，我们的研究有助于提高对纳米晶体在体内命运的理解。
SNX-2112 is a promising anticancer agent but has poor solubility in both water and oil. In the study reported here, we aimed to develop a nanocrystal formulation for SNX-2112 and to determine the pharmacokinetic behaviors of the prepared nanocrystals. Nanocrystals of SNX-2112 were prepared using the wet-media milling technique and characterized by particle size, differential scanning calorimetry, drug release, etc. Physiologically based pharmacokinetic (PBPK) modeling was undertaken to evaluate the drug’s disposition in rats following administration of drug cosolvent or nanocrystals. The optimized SNX-2112 nanocrystals (with poloxamer 188 as the stabilizer) were 203 nm in size with a zeta potential of −11.6 mV. In addition, the nanocrystals showed a comparable release profile to the control (drug cosolvent). Further, the rat PBPK model incorporating the parameters of particulate uptake (into the liver and spleen) and of in vivo drug release was well fitted to the experimental data following administration of the drug nanocrystals. The results reveal that the nanocrystals rapidly released drug molecules in vivo, accounting for their cosolvent-like pharmacokinetic behaviors. Due to particulate uptake, drug accumulation in the liver and spleen was significant at the initial time points (within 1 hour). The nanocrystals should be a good choice for the systemic delivery of the poorly soluble drug SNX-2112. Also, our study contributes to an improved understanding of the in vivo fate of nanocrystals.