Mechanism of Inhibition of P-Glycoprotein Mediated Efflux by Vitamin E TPGS: Influence on ATPase Activity and Membrane Fluidity
详细信息 查看全文
- 作者：Eva-Maria Collnot ; Christiane Baldes ; Michael F. Wempe ; Reinhard Kappl ; Jü ; rgen Hü ; ttermann ; John A. Hyatt ; Kevin J. Edgar ; Ulrich F. Schaefer ; Claus-Michael Lehr
- 刊名：Molecular Pharmaceutics
- 出版年：2007
- 出版时间：June 2007
- 年：2007
- 卷：4
- 期：3
- 页码：465 - 474
- 全文大小：176K
- 年卷期：v.4,no.3(June 2007)
- ISSN：1543-8392
文摘
Efflux pump (e.g., P-gp, MRP1, and BCRP) inhibition has been recognized as astrategy to overcome multi-drug resistance and improve drug bioavailability. Besides small-molecule inhibitors, surfactants such as Tween 80, Cremophor EL, several Pluronics, and VitaminE TPGS (TPGS 1000) are known to modulate efflux pump activity. Competitive inhibition ofsubstrate binding, alteration of membrane fluidity, and inhibition of efflux pump ATPase havebeen proposed as possible mechanisms. Focusing on TPGS 1000, the aim of our study was tounravel the inhibitory mechanism by comparing the results of inhibition experiments in a Caco-2transport assay with data from electron spin resonance (ESR) and from ATPase activity studies.ESR results, on Caco-2 cells using 5-doxyl stearic acid (5-SA) as a spin probe, ruled out cellmembrane fluidization as a major contributor; change of membrane fluidity was only observedat surfactant concentrations 100 times higher than those needed to achieve full efflux inhibition.Concurrently, TPGS 1000 inhibited substrate induced ATPase activity without inducing significantATPase activity on its own. By investigating TPGS analogues that varied by their PEG chainlength, and/or possessed a modified hydrophobic core, transport studies revealed that modulationof ATPase activity correlated with inhibitory potential for P-gp mediated efflux. Hence, theseresults indicate that ATPase inhibition is an essential factor in the inhibitory mechanism ofTPGS 1000 on cellular efflux pumps.