title: Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers.
abstract: BACKGROUND
  Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1 B 1 (OATP 1 B 1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin.
  
  
  METHODS
  Twenty-four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1--8 mg) were further investigated. Subjects were grouped according to OATP 1 B 1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics.
  
  
  RESULTS
  Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8+/-13.3, 54.4 +/-12.4, and 68.1+/-6.3 ng.h.mL(-1).mg(-1) (mean+/-SD), respectively, with significant differences between all 3 groups (P=.008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin C(max) values were 13.2+/- 3.3, 18.2+/-5.7, and 29.4+/- 9.6 ng.mL(-1).mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P=.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C(max) values of pitavastatin lactone.
  
  
  CONCLUSIONS
  OATP 1 B 1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP 1 B 1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology Unit, Seoul National University College of Medicine and Hospital, and Choongwae Pharma.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Chung
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.forename: Jung-Ryul
authors.initials: JR
authors.lastname: Kim
authors.forename: Dal-Seok
authors.initials: DS
authors.lastname: Oh
authors.forename: Hye-Ryung
authors.initials: HR
authors.lastname: Jung
authors.forename: Kyoung-Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Ki-Ho
authors.initials: KH
authors.lastname: Moon
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
mesh_terms: D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006207:Half-Life; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D007723:Korea; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011804:Quinolines; C503999:SLCO1B1 protein, human; C108475:pitavastatin