title: CYP2C9*3(1075A > C), ABCB1 and SLCO1B1 genetic polymorphisms and gender are determinants of inter-subject variability in pitavastatin pharmacokinetics.
abstract: A pharmacokinetics study was conducted in 12 Chinese volunteers following a single dose of 1 mg, 2 mg and 4 mg of pitavastatin calcium in an open-label, randomized, three-period crossover design. Plasma concentrations of pitavastatin acid and pitavastatin lactone were determined by a HPLC method. Single-nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLCO1B1, CYP2C9 and CYP3A5 were determined by TaqMan (MGB) genotyping assay. An analysis was performed on the relationship between the aforementioned SNPs and dose-normalized (based on 1 mg) area under the plasma concentration-time curve extrapolated to infinity [AUC(0-infinity)] and peak plasma concentration (Cmax) values of the acid and lactone forms of pitavastatin. Pitavastatin exhibited linear pharmacokinetics and great inter-subject variability. Compared to CYP2C9*1/*1 carriers, CYP2C9*1/*3 carriers had higher AUC(0-infinity) and Cmax of pitavastatin acid and AUC(0-infinity) of pitavastatin lactone (P<0.05). With respect to ABCB1 G2677T/A, non-G carriers had higher Cmax and AUC(0-infinity) of pitavastatin acid, and Cmax of pitavastatin lactone compared to GT, GA or GG genotype carriers (P<0.05). Gene-dose effects of SLCO1B1 c.521T> C and g.11187G > A on pharmacokinetics of the acid and lactone forms were observed. Compared to non-SLCO1B1*17 carriers, SLCO1B1*17 carriers had higher Cmax and AUC(0-infinity) of the acid and lactone forms (P<0.05). Significant sex difference was observed for pharmacokinetics of the lactone. Female SLCO1B1 521TT subjects had higher Cmax and AUC(0-infinity) of pitavastatin lactone compared to male 521TT subjects, however, such gender difference disappeared in 521 TC and 521CC subjects. Pitavastatin pharmacokinetics was not significantly affected by ABCB1 C1236T, ABCB1C3435T, CYP3A5*3, ABCG2 c.34G > A, c.421C > A, SLCO1B1 c.388A>G, c.571T>C and c.597C>T. We conclude that CYP2C9*3, ABCB1 G2677T/A, SLCO1B1 c.521T>C, SLCO1B1 g.11187G > A, SLCO1B1*17 and gender contribute to inter-subject variability in pitavastatin pharmacokinetics. Personalized medicine should be necessary for hypercholesterolaemic patients receiving pitavastatin.
authors.affiliation: Department of Pharmacy, the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
authors.forename: Qiu-Xia
authors.initials: QX
authors.lastname: Chen
authors.forename: Zou-Rong
authors.initials: ZR
authors.lastname: Ruan
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Xu
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006207:Half-Life; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007783:Lactones / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011804:Quinolines / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011804:Quinolines; C503999:SLCO1B1 protein, human; D004247:DNA; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C108475:pitavastatin