Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Drug Transporters in ADME, Department of Pharmacy, Faculty of Health and Medical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Int J Pharm. 2018 May 30;543(1-2):352-360. doi: 10.1016/j.ijpharm.2018.04.006. Epub 2018 Apr 7.
The aim of the present work was to investigate the ability of nonionic surfactants to increase the oral absorption of the P-glycoprotein substrate etoposide in vitro and in vivo. Intestinal absorption was investigated by studying bidirectional permeability of etoposide across filter-grown Caco-2 and MDCKII MDR1 cell monolayers. The oral absorption of etoposide was investigated in wild type (WT) and mdr1a deficient (KO) Sprague-Dawley rats. In cell cultures, polysorbate 20 (PS20) decreased P-glycoprotein mediated efflux of etoposide. When PS20 and etoposide were co-administered to WT rats, the oral absorption of etoposide increased significantly in the presence of 5 and 25% (v/v) PS20. However, in KO rats, the exposure of etoposide after oral co-administration with 5% PS20 was similar to control. Unexpectedly, co-administration of etoposide with 25% PS20 significantly reduced the absorption fraction of etoposide in mdr1a KO rats. In vitro dialysis studies performed on PS20-containing etoposide solutions suggested that the reduced bioavailability may be due to etoposide retention in PS20 micelles and/or through increased viscosity. In conclusion, PS20 increases oral bioavailability of etoposide through inhibition of P-glycoprotein. However, the use of the excipient may be challenged by etoposide retention at higher concentrations.
本研究旨在探讨非离子表面活性剂对 P 糖蛋白底物依托泊苷体外和体内口服吸收的增强作用。通过研究依托泊苷在 Caco-2 和 MDCKII MDR1 细胞单层中的双向渗透性来研究肠道吸收。在野生型 (WT) 和 mdr1a 缺陷型 (KO) Sprague-Dawley 大鼠中研究了依托泊苷的口服吸收。在细胞培养物中，聚山梨醇酯 20 (PS20) 降低了 P 糖蛋白介导的依托泊苷外排。当 PS20 和依托泊苷同时给予 WT 大鼠时，在存在 5%和 25%（v/v）PS20 的情况下，依托泊苷的口服吸收显著增加。然而，在 KO 大鼠中，与对照相比，口服给予 5% PS20 后依托泊苷的暴露量相似。出乎意料的是，在 mdr1a KO 大鼠中，同时给予依托泊苷和 25% PS20 显著降低了依托泊苷的吸收分数。在含有 PS20 的依托泊苷溶液上进行的体外透析研究表明，生物利用度降低可能是由于依托泊苷保留在 PS20 胶束中和/或通过增加粘度。总之，PS20 通过抑制 P 糖蛋白增加依托泊苷的口服生物利用度。然而，由于在较高浓度下依托泊苷的保留，可能会对赋形剂的使用提出挑战。
