Novel in vitro transport method for screening the reversibility of P-glycoprotein inhibitors

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• 作者：Kesinee Netsomboon ; Flavia Laffleur ; Wongsakorn Suchaoin ; Andreas Bernkop-Schnü ; rch ; ^{andreas.bernkop@uibk.ac.at" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Verapamil ; Cyclosporin A ; Ritonavir ; Quinidine ; N-ethylmaleimide ; Cremophor® ; EL ; Tween 80 ; Preactivated thiomers ; Rhodamine 123 ; Caco-2
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：100
• 期：Complete
• 页码：9-14
• 全文大小：635 K

文摘

The purpose of this study was to establish a novel in vitro method for screening reversibility of P-glycoprotein (P-gp) inhibitors. Caco-2 cells with 21 days of cultivation were used as an in vitro model. Transport of rhodamine 123 in the presence of various inhibitors and after removing of inhibitors was determined. Transport of rhodamine 123 at 4 °C and in the secretory direction assured that Caco-2 cells exhibited P-gp function at all time of experiment. The apparent permeability coefficient (P_app) of rhodamine 123 in the presence of verapamil, cyclosporin A, ritonavir, quinidine, N-ethylmaleimide, Cremophor® EL, Tween 80 and poly(acrylic acid)-cysteine-2-mercaptonicotinic acid (PAA-cys-2MNA) was 2.3-, 3.8-, 2.3-, 3.1, 7.5-, 2.1-, 2.9- and 2.5-fold higher than P_app of rhodamine 123 alone. After removing of the inhibitors, P_app decreased to the same range of control except in the case of N-ethylmaleimide which was 2.4-fold higher than the control. These results revealed a reversible inhibition of verapamil, cyclosporin A, ritonavir, quinidine, Cremophor® EL, Tween 80 and PAA-cys-2MNA and an irreversible inhibition of N-ethylmaleimide for P-gp. Thus, this novel established that in vitro method might be an effective tool for screening the reversibility of inhibition of P-gp inhibitors.