Back to Search
Start Over
CYP2C9*3(1075AC), ABCB1 and SLCO1B1 genetic polymorphisms and gender are determinants of inter-subject variability in pitavastatin pharmacokinetics
- Source :
- Die Pharmazie. 68(3)
- Publication Year :
- 2013
-
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 (P0.05). 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 (P0.05). Gene-dose effects of SLCO1B1 c.521TC and g.11187GA 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 (P0.05). 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.34GA, c.421CA, SLCO1B1 c.388AG, c.571TC and c.597CT. We conclude that CYP2C9*3, ABCB1 G2677T/A, SLCO1B1 c.521TC, SLCO1B1 g.11187GA, SLCO1B1*17 and gender contribute to inter-subject variability in pitavastatin pharmacokinetics. Personalized medicine should be necessary for hypercholesterolaemic patients receiving pitavastatin.
- Subjects :
- Adult
Male
ATP Binding Cassette Transporter, Subfamily B
Genotype
Organic Anion Transporters
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Lactones
Young Adult
Asian People
Humans
ATP Binding Cassette Transporter, Subfamily B, Member 1
Cytochrome P-450 CYP2C9
Sex Characteristics
Cross-Over Studies
Polymorphism, Genetic
Liver-Specific Organic Anion Transporter 1
Reproducibility of Results
DNA
Haplotypes
Area Under Curve
Quinolines
Female
Aryl Hydrocarbon Hydroxylases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Half-Life
Subjects
Details
- ISSN :
- 00317144
- Volume :
- 68
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Die Pharmazie
- Accession number :
- edsair.pmid..........32abdae02f88ea35f5f9b8fbdaccee9e