title: Intestinal absorption of HMG-CoA reductase inhibitor pravastatin mediated by organic anion transporting polypeptide.
abstract: OBJECTIVE
  The purpose of this study is to clarify the impact of organic anion transporting polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin.
  
  
  METHODS
  OATP/Oatp-mediated pravastatin uptake was evaluated with Xenopus oocytes systems. Intestinal permeability was measured by an in situ closed loop method in rats. In vivo pravastatin absorption was kinetically assessed by measuring plasma concentration after oral administration in rats.
  
  
  RESULTS
  Uptake of pravastatin by Oatp1a5, Oatp2b1, OATP1A2, and OATP2B1 cRNA-injected Xenopus oocytes was significantly increased compared with that by water-injected oocytes. Naringin, a potent inhibitor of Oatps and Mdr1, decreased the Oatp1a5-mediated uptake of pravastatin with IC (50) value of 30.4 μM. Rat intestinal permeability of pravastatin was significantly reduced in the presence of 1,000 μM naringin. Similar results were obtained in in vivo absorption studies in rats. Furthermore, no significant change in the permeability was observed in the presence of elacridar, a potent inhibitor of both Mdr1 and Bcrp, though the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Mdr1 and Bcrp are not involved in intestinal absorption of pravastatin.
  
  
  CONCLUSIONS
  Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats.
authors.affiliation: Faculty of Pharmacy, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Kensuke
authors.initials: K
authors.lastname: Suzuki
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001692:Biological Transport; D002853:Chromatography, Liquid; D044950:Flavanones / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D007082:Ileum / Q000378:metabolism*; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017035:Pravastatin / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry; D014982:Xenopus laevis
chemical_list: D044950:Flavanones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D017035:Pravastatin; C005274:naringin