title: Effects of the SLCO1B1*15 allele on the pharmacokinetics of pitavastatin.
abstract: The hepatic uptake of pitavastatin is mediated by carriers, especially OATP1B1, which is encoded by the SLCO1B1 gene. Because the liver is a target organ of pitavastatin, OATP1B1 is responsible for both the pharmacological effects and clearance of pitavastatin. The effects of the SLCO1B1*15 allele on the pharmacokinetics (PK) of pitavastatin were studied. Pitavastatin 2 mg was orally administered to 38 subjects with SLCO1B1*1a/*1b (n = 20), *1b/*15 (n = 13), or *15/*15 (n = 5). After pitavastatin administration, the plasma concentrations of pitavastatin and pitavastatin lactone were assayed for up to 48 h using liquid chromatography-tandem mass spectrometry. In comparison to the SLCO1B1*1a/*1b subjects, only a C(max) was slightly higher in the SLCO1B1*1b/*15 subjects. However, the SLCO1B1*15/*15 subjects had a 1.74-fold higher AUC(inf) (285.5 ± 14.5 vs. 164.6 ± 41.3 ng·h/mL; p < 0.001), a 2.21-fold higher C(max) (106.7 ± 15.1 vs. 48.3 ± 13.4 ng/mL; p < 0.001), and a 47.3% lower apparent oral clearance (13.1 ± 3.9 vs. 6.9 ± 0.4 L/h; p < 0.001) of pitavastatin. For pitavastatin lactone, there were no significant differences in AUC(inf), C(max), t(1/2), and t(max) among the three genotypes. Unlike previous studies, the disposition of pitavastatin exposure was not altered in subjects with the SLCO1B1*1b/*15 genotype, except C(max). However, pitavastatin exposure was significantly increased in subjects with the SLCO1B1*15/*15 genotype due to reduced hepatic absorption.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Chang-Ik
authors.initials: CI
authors.lastname: Choi
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Lee
authors.forename: Hye-In
authors.initials: HI
authors.lastname: Lee
authors.forename: Bo-Hye
authors.initials: BH
authors.lastname: Kim
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Bae
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000483:Alleles; D004305:Dose-Response Relationship, Drug; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000235:genetics*; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011804:Quinolines; C503999:SLCO1B1 protein, human; C108475:pitavastatin