Nielsen Carsten Uhd, Abdulhussein Ahmed A, Colak Dilan, Holm René
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Int J Pharm. 2016 Nov 20;513(1-2):78-87. doi: 10.1016/j.ijpharm.2016.09.011. Epub 2016 Sep 4.
The aim was to investigate the ability of polysorbate 20 to alter oral digoxin absorption in vitro and drug exposure in vivo via modulation of transporter mediated efflux. Transport studies were performed in MDCKII-MDR1 and Caco-2 cells using H-digoxin. Pharmacokinetic studies were performed in wild type and mdr1a deficient Sprague Dawley rats. H-digoxin was quantified using liquid scintillation counting. The results showed an increased absorptive transport and a reduced secretory transport in MDCKII-MDR and Caco-2 cells as a function of polysorbate 20 concentrations. The secretory transport (B-A) of digoxin was reduced by 50% at lower polysorbate 20 concentrations than required to increase the absorptive transport (A-B). In vivo, the oral bioavailability of digoxin in wild type animal was increased by 10-25% (w/v) polysorbate 20. In mdr1a deficient Sprague Dawley rats 25% (w/v) polysorbate 20 did not alter the absorption of digoxin after oral administration, but digoxin exposure was significantly different between wild type and mdr1a deficient rats. In conclusion, polysorbate 20 increased absorptive transport across Caco-2 cell monolayers and in vivo in rats in a concentration dependent manner, most likely via inhibition of P-gp rather than through solubilization of digoxin.
目的是研究聚山梨醇酯20通过调节转运体介导的外排作用改变地高辛体外口服吸收及体内药物暴露的能力。使用H-地高辛在MDCKII-MDR1和Caco-2细胞中进行转运研究。在野生型和mdr1a缺陷型Sprague Dawley大鼠中进行药代动力学研究。使用液体闪烁计数法定量H-地高辛。结果表明，在MDCKII-MDR和Caco-2细胞中，随着聚山梨醇酯20浓度的变化，吸收性转运增加，分泌性转运减少。与增加吸收性转运（A-B）所需的聚山梨醇酯20浓度相比，较低浓度的聚山梨醇酯20即可使地高辛的分泌性转运（B-A）降低50%。在体内，野生型动物中地高辛的口服生物利用度因10-25%（w/v）的聚山梨醇酯20而增加。在mdr1a缺陷型Sprague Dawley大鼠中，25%（w/v）的聚山梨醇酯20在口服给药后未改变地高辛的吸收，但野生型和mdr1a缺陷型大鼠之间的地高辛暴露存在显著差异。总之，聚山梨醇酯20以浓度依赖性方式增加了跨Caco-2细胞单层的吸收性转运以及大鼠体内的吸收性转运，最有可能是通过抑制P-糖蛋白，而非通过增溶地高辛。
