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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\u2009week pretreatment with piperine. Compared with the control group given diltiazem (20\u2009mg\/kg) alone, the pretreatment with piperine (10 or 20\u2009mg\/kg, once daily for 2\u2009weeks) decreased the oral exposure of diltiazem by 36\u201348% in rats. Consequently, the bioavailability of oral diltiazem was significantly lower (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) after the 2\u2009week pretreatment with piperine. The pretreatment with piperine for 2\u2009weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by a significant decrease in the metabolite\u2013parent 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\u2010gp was significantly enhanced after the 2\u2009week pretreatment with piperine in rats. In addition, piperine increased the PXR reporter activity in human hepatoma cells. Taken together, the 2\u2009week pretreatment with piperine significantly induced intestinal P\u2010gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats. Copyright \u00a9 2012 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/bdd.1811","type":"journal-article","created":{"date-parts":[[2012,8,28]],"date-time":"2012-08-28T05:51:36Z","timestamp":1346133096000},"page":"446-454","source":"Crossref","is-referenced-by-count":27,"title":["Repeated dosing of piperine induced gene expression of P\u2010glycoprotein via stimulated pregnane\u2010X\u2010receptor activity and altered pharmacokinetics of diltiazem in rats"],"prefix":"10.1002","volume":"33","author":[{"given":"Fu","family":"Qiang","sequence":"first","affiliation":[{"name":"College of Pharmacy Dongguk University Pil\u2010dong\u20103\u2010ga, Jung\u2010gu Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keon\u2010Wook","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Seoul National University 1 Gwanak\u2010ro, Gwanak\u2010gu Seoul 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