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

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 3648% 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 metaboliteparent 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. Copyright (c) 2012 John Wiley & Sons, Ltd.