title: Repeated dosing of piperine induced gene expression of P-glycoprotein via stimulated pregnane-X-receptor activity and altered pharmacokinetics of diltiazem in rats.
abstract: 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.
authors.affiliation: College of Pharmacy, Dongguk University, Pil-dong-3-ga, Seoul, Korea.
authors.forename: Fu
authors.initials: F
authors.lastname: Qiang
authors.forename: Keon-Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000470:Alkaloids / Q000008:administration & dosage*; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage*; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics*; D004110:Diltiazem / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D010880:Piperidines / Q000008:administration & dosage*; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage*; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D052117:Benzodioxoles; D002121:Calcium Channel Blockers; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C037769:deacetyldiltiazem; D004110:Diltiazem; C008922:piperine