Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Quantitative Sciences, Janssen R&D, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Int J Pharm. 2020 Jun 15;583:119399. doi: 10.1016/j.ijpharm.2020.119399. Epub 2020 May 4.
It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic® F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide's solubility approximately 100 times (16 mg mL) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg), AUC and C were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg. A single oral dose of 20 mg kg zosuquidar followed by 20 mg kg oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide.
有人提出，通过使 P-糖蛋白（P-gp）饱和，可以增加低渗透性 P-gp 底物的口服吸收。对于 BCS 分类为 IV 类的药物，由于低水溶解度，使 P-gp 饱和具有挑战性。本研究调查了 BCS IV 类药物依托泊苷是否可以在口服后被溶解到饱和 P-gp 的浓度。一种由 10%（w/v）的 Pluronic® F-127 和聚乙烯吡咯烷酮/醋酸乙烯酯（PVP/VA）以及 57%（v/v）乙醇组成的制剂，将依托泊苷的溶解度提高了约 100 倍（16mg/mL），与水溶解度相比。在体外，该制剂在模拟肠液中稀释时是稳定的。在雄性 Sprague-Dawley 大鼠中，使用该制剂基质口服给予递增的溶解依托泊苷剂量，使依托泊苷剂量比例的 AUC 呈剂量依赖性增加，但与对照相比，绝对口服生物利用度（F）和吸收率较低。在所研究的最高剂量（100mg/kg）下，AUC 和 C 分别比对照剂量（20mg/kg）显著增加了 2.9 倍和 1.4 倍。单次口服 20mg/kg 的佐舒奎达后再口服 20mg/kg 的依托泊苷，可使 F 增加 8.6 倍。总之，开发了一种具有改善依托泊苷溶解度的稳定制剂，但该制剂并未导致依托泊苷的口服生物利用度增加。
