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Repeated dosing of piperine induced the gene expression of P-glycoprotein via the stimulated Pregnane-X-receptor activity and altered the pharmacokinetics of diltiazem in rats.

Biopharm Drug Dispos. 2012 Aug 28;

Authors: Qiang F, Kang KW, Han HK


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 to 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) under the 2-week pretreatment with piperine. The pretreatment with piperine for two weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by the 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 PXR reporter activity in human hepatoma cells. Taken all together, 2-week pretreatment with piperine significantly induced the intestinal P-gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats. Copyright © 2012 John Wiley & Sons, Ltd.

PMID: 22927137 [PubMed - as supplied by publisher]