title: Intestinal absorption of HMG-CoA reductase inhibitor pitavastatin mediated by organic anion transporting polypeptide and P-glycoprotein/multidrug resistance 1.
abstract: The purpose of this study was to investigate the involvement of organic anion transporting polypeptide (OATP/Oatp) and P-glycoprotein (P-gp)/multidrug resistance 1 (MDR1/Mdr1) in intestinal absorption of pitavastatin. Pitavastatin was found to be a substrate for human OATP1A2, OATP2B1, and MDR1 and rat Oatp1a5, Oatp2b1, and Mdr1a in experiments using transporter-expressing Xenopus oocytes and LLC-PK1 cell systems. Naringin inhibited Oatp1a5- and Mdr1a-mediated transport of pitavastatin with IC(50) values of 18.5 and 541 µM, respectively. The difference in the IC(50) values of naringin for Oatp1a5 and Mdr1a-mediated pitavastatin transport may account for the complex concentration-dependent effect of naringin on the intestinal absorption of pitavastatin. Rat intestinal permeability of pitavastatin measured by the in situ closed-loop perfusion method was indeed significantly reduced by 200 µM naringin, but was significantly increased by 1000 µM naringin. Furthermore, the permeability was significantly increased by elacridar, a potent inhibitor of Mdr1, while the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Oatp1a5 and Mdr1a are both involved in intestinal absorption of pitavastatin. Our present results indicate that OATP/Oatp and MDR1/Mdr1 play roles in the intestinal absorption of pitavastatin as influx and efflux transporters, respectively.
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Kensuke
authors.initials: K
authors.lastname: Suzuki
authors.forename: Megumi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D004347:Drug Interactions; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D007408:Intestinal Absorption / Q000187:drug effects*; D018374:LLC-PK1 Cells; D008297:Male; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines; D014981:Xenopus
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044950:Flavanones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C513055:ABCB1 protein, human; C512988:SLCO1A2 protein, human; C450859:SLCO2B1 protein, human; C533062:Slco2b1 protein, rat; C108475:pitavastatin; C083501:Elacridar; C005274:naringin