Trantinterol, a Novel 尾2-Adrenoceptor Agonist, Noncompetitively Inhibits P-Glycoprotein Function in Vitro and in Vivo
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- 作者：Tingting Wang ; Yantong Sun ; Wenxiao Ma ; Zhichao Yang ; Junfeng Yang ; Jingrui Liu ; Hongbo Fan ; Yan Yang ; Jingkai Gu ; John Paul Fawcett ; Yingjie Guo
- 刊名：Molecular Pharmaceutics
- 出版年：2015
- 出版时间：January 5, 2015
- 年：2015
- 卷：12
- 期：1
- 页码：1-9
- 全文大小：392K
- ISSN：1543-8392
文摘
P-glycoprotein (P-gp)-mediated drug鈥揹rug interactions are important factors causing adverse effects of drugs in clinical use. The aim of this study was to determine whether trantinterol (also known as SPFF), a novel 尾2-adrenoceptor agonist, was a P-gp inhibitor or substrate. The results showed that trantinterol was not a substrate of P-gp but increased rhodamine 123 (Rho 123) uptake by MDCK-MDR1 cells and decreased the efflux transport of both Rho 123 and cyclosporine A (CsA) in bidirectional transport studies across MDCK-MDR1 cell monolayers. This suggested that trantinterol was a P-gp inhibitor but not a P-gp substrate. The mechanism of inhibition was investigated in the P-gp-Glo assay system, where it was found that trantinterol inhibited P-gp ATPase activity in a dose-dependent manner. A subsequent study using the antibody binding assay with the conformation-sensitive P-gp-specific antibody UIC2 confirmed that trantinterol decreased UIC2 binding at 10 渭M in contrast to the competitive inhibitor, verapamil. This suggested that trantinterol was a noncompetitive inhibitor of P-gp. Finally, a pharmacokinetic study in rat showed that trantinterol significantly increased the area under the plasma concentration鈥搕ime curve (AUC) and maximum plasma concentration (Cmax) of digoxin and paclitaxel (PAC), and the Cmax of cyclosporine A (CsA). In summary, trantinterol is a potent noncompetitive P-gp inhibitor which may increase the bioavailability of other P-gp substrate drugs coadministered with it.