Enhancement effect of P-gp inhibitors on the intestinal absorption and antiproliferative activity of bestatin

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• 作者：Xiaokui Huo ; Qi Liu ; Changyuan Wang ; Qiang Meng ; Huijun Sun ; Jinyong Peng ; Xiaochi Ma ; Kexin Liu
• 关键词：P-gp ; Bestatin ; Intestinal absorption ; Antiproliferative activity
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2013
• 出版时间：20 November, 2013
• 年：2013
• 卷：50
• 期：3-4
• 页码：420-428
• 全文大小：1096 K

文摘

Bestatin is an immunomodulator with antitumor activity. This study was performed to investigate the effect of P-gp on the intestinal absorption and antiproliferative activity of bestatin. Our results showed that P-gp inhibitors significantly increased rat intestinal absorption of bestatin in vivo and in vitro. The net efflux ratio of bestatin was 2.2 across mock-/MDR1-MDCK cell monolayers and was decreased by P-gp inhibitors, indicating bestatin was a substrate of P-gp. Furthermore, the IC50 values of bestatin on U937 and K562 cells were decreased dramatically and the intracellular concentrations of bestatin were increased by incubation of cells with verapamil or Cyclosporin A. K562/ADR cells exhibited a higher IC50 value and a lower intracellular level of bestatin. The bestatin level in K562/ADR cells was partially restored by incubation with doxorubicin. However, P-gp and APN mRNA levels were not changed by bestatin. These results suggested that the intestinal absorption and accumulation in cancer cells for bestatin were limited by P-gp-mediated efflux. Additional attention should be paid to the alternative exposure of bestatin when bestatin was coadministered with drugs as P-gp substrates in clinic.