Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GF , United Kingdom.
Department of Chemistry , University of Liverpool , Liverpool L69 7ZD , United Kingdom.
Mol Pharm. 2018 Nov 5;15(11):4835-4842. doi: 10.1021/acs.molpharmaceut.8b00482. Epub 2018 Oct 23.
Pharmaceutical excipients are no longer considered inert and have been shown to influence the activity of metabolic enzymes and transporters, resulting in altered pharmacokinetics of substrate drugs. In this study, the effect of 25 excipients commonly used in drug formulations were investigated for their effect on P-glycoprotein (P-gp) activity. The effect of excipients on P-gp were assessed by measuring the change in the cellular accumulation of a P-gp substrate, digoxin, in MDCK-MDR1 (Madin Darby canine kidney transfected with multidrug resistance 1 gene) cells. The cells were exposed to low (10 μM) and high (200 μM) concentrations of excipient along with 10 μM digoxin. Excipient concentrations were chosen to span the range of concentrations previously used for investigating activities in vitro. At 10 μM of excipient, an increase in the intracellular digoxin concentration was seen with d-α-tocopherol poly-(ethylene glycol) succinate (Vit-E-PEG; p = 0.002), poly(ethylene oxide) sorbitan monooleate (Tween 80; p = 0.001), cetyltrimethylammonium bromide (CTAB; p = 0.021), poly(ethylene oxide) modified castor oil (Cremophor EL; p = 0.01), polyethylene glycol-hydroxystearate (Solutol HS 15; p = 0.006), and poly(ethylene glycol) hexadecyl ether (Brij 58; p = 0.001). At 200 μM, Vit-E-PEG ( p < 0.0001), sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT; p < 0.0001), Tween 80 ( p < 0.0001), CTAB ( p = 0.004), poly(ethylene oxide) sorbitan monolaurate (Tween 20; p < 0.0001), Cremophor EL ( p < 0.0001), Solutol HS 15 ( p < 0.0001), Brij 58 ( p < 0.0001), and sodium carboxymethyl cellulose (NaCMC; p = 0.006) increased intracellular digoxin significantly. Concentration-dependent inhibition of P-gp was then investigated for selected excipients giving an IC for Vit-E-PEG (12.48 μM), AOT (192.5 μM), Tween 80 (45.29 μM), CTAB (96.67 μM), Tween 20 (74.15 μM), Cremophor EL (11.92 μM), Solutol HS 15 (179.8 μM), Brij 58 (25.22 μM), and NaCMC (46.69 μM). These data add to the growing body of evidence demonstrating that not all excipients are inert and will aid excipient choice for rational formulation development.
药物辅料不再被认为是惰性的，它们已被证明会影响代谢酶和转运蛋白的活性，从而改变底物药物的药代动力学。在这项研究中，研究了 25 种常用于药物制剂的辅料对 P-糖蛋白 (P-gp) 活性的影响。通过测量 P-糖蛋白底物地高辛在 MDCK-MDR1（转染了多药耐药基因 1 的犬肾细胞）细胞中的细胞内积累变化来评估辅料对 P-gp 的影响。将细胞暴露于低（10 μM）和高（200 μM）浓度的辅料以及 10 μM 地高辛中。选择辅料浓度范围以涵盖先前用于体外活性研究的浓度范围。在 10 μM 的辅料浓度下，d-α-生育酚聚（乙二醇）琥珀酸酯（Vit-E-PEG；p = 0.002）、聚氧乙烯失水山梨醇单油酸酯（吐温 80；p = 0.001）、十六烷基三甲基溴化铵（CTAB；p = 0.021）、聚乙二醇改性蓖麻油（Cremophor EL；p = 0.01）、聚乙二醇羟基硬脂酸酯（Solutol HS 15；p = 0.006）和聚乙二醇十六烷基醚（Brij 58；p = 0.001）增加了细胞内地高辛的浓度。在 200 μM 时，Vit-E-PEG（p < 0.0001）、1,4-双（2-乙基己氧基）-1,4-二氧丁烷-2-磺酸钠（AOT；p < 0.0001）、吐温 80（p < 0.0001）、CTAB（p = 0.004）、聚氧乙烯失水山梨醇单月桂酸酯（吐温 20；p < 0.0001）、Cremophor EL（p < 0.0001）、Solutol HS 15（p < 0.0001）、Brij 58（p < 0.0001）和羧甲基纤维素钠（NaCMC；p = 0.006）显著增加了细胞内地高辛的浓度。然后研究了选定辅料的浓度依赖性 P-gp 抑制作用，结果表明 Vit-E-PEG（12.48 μM）、AOT（192.5 μM）、吐温 80（45.29 μM）、CTAB（96.67 μM）、吐温 20（74.15 μM）、Cremophor EL（11.92 μM）、Solutol HS 15（179.8 μM）、Brij 58（25.22 μM）和 NaCMC（46.69 μM）对 P-gp 有抑制作用。这些数据增加了越来越多的证据，证明并非所有辅料都是惰性的，这将有助于选择辅料进行合理的配方开发。
