College of Pharmacy, Dongguk University, Pil-dong-3-ga, Seoul, Korea.
Biopharm Drug Dispos. 2012 Nov;33(8):446-54. doi: 10.1002/bdd.1811. Epub 2012 Sep 18.
This study investigated the effect of piperine on the gene expression of P-glycoprotein (P-gp) as well as pregnane-X-receptor (PXR) activity and also its implication on the bioavailability of diltiazem, a P-gp substrate. The effect of piperine on the systemic exposure of diltiazem was examined in rats after the intravenous and oral administration of diltiazem with/without 2 week pretreatment with piperine. Compared with the control group given diltiazem (20 mg/kg) alone, the pretreatment with piperine (10 or 20 mg/kg, once daily for 2 weeks) decreased the oral exposure of diltiazem by 36-48% in rats. Consequently, the bioavailability of oral diltiazem was significantly lower (p < 0.05) after the 2 week pretreatment with piperine. The pretreatment with piperine for 2 weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by a significant decrease in the metabolite-parent ratio. In contrast to the oral pharmacokinetics, piperine did not affect the intravenous pharmacokinetics of diltiazem in rats. Immunoblot analysis indicated that the protein expression level of intestinal P-gp was significantly enhanced after the 2 week pretreatment with piperine in rats. In addition, piperine increased the PXR reporter activity in human hepatoma cells. Taken together, the 2 week pretreatment with piperine significantly induced intestinal P-gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats.
本研究探讨了胡椒碱对 P-糖蛋白（P-gp）基因表达以及孕烷 X 受体（PXR）活性的影响，以及其对 P-gp 底物地尔硫䓬生物利用度的影响。在给予地尔硫䓬（20mg/kg）静脉和口服后，用/不用胡椒碱预处理 2 周，在大鼠体内研究了胡椒碱对地尔硫䓬系统暴露的影响。与单独给予地尔硫䓬（20mg/kg）的对照组相比，胡椒碱（10 或 20mg/kg，每天一次，预处理 2 周）使大鼠口服地尔硫䓬的暴露量降低了 36-48%。因此，胡椒碱预处理 2 周后，口服地尔硫䓬的生物利用度显著降低（p < 0.05）。胡椒碱预处理 2 周还使地尔硫䓬的主要活性代谢物去乙酰地尔硫䓬的全身暴露量减少了约 73%，同时代谢物-母体比显著降低。与口服药代动力学相反，胡椒碱对大鼠静脉内给予地尔硫䓬的药代动力学没有影响。免疫印迹分析表明，胡椒碱预处理 2 周后，大鼠肠道 P-gp 蛋白表达水平显著增强。此外，胡椒碱增加了人肝癌细胞中的 PXR 报告基因活性。综上所述，胡椒碱预处理 2 周可显著诱导肠道 P-gp 表达，同时刺激 PXR 活性，降低大鼠口服地尔硫䓬和去乙酰地尔硫䓬的暴露量。
