CYP2C9&z.ast;3(1075A > C), ABCB1 and SLCO1B1 genetic polymorphisms and gender are determinants of inter-subject variability in pitavastatin pharmacokinetics

摘要

A pharmacokinetics study was conducted in 12 Chinese volunteers following a single dose of 1 mg, 2mg and 4mg 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. Singlenucleotide 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-??)] 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&z.ast;1/&z.ast;1 carriers, CYP2C9&z.ast;1/&z.ast;3 carriers had higher AUC(0-??) and Cmax of pitavastatin acid and AUC(0-??) of pitavastatin lactone (P 0.05). With respect to ABCB1 G2677T/A, non-G carriers had higher Cmax and AUC(0-??) 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&z. ast;17 carriers, SLCO1B1&z.ast;17 carriers had higher Cmax and AUC(0-??) 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-??) of pitavastatin lactone compared to male 521TT subjects, however, such gender difference disappeared in 521TC and 521CC subjects. Pitavastatin pharmacokineticswas not significantly affected by ABCB1 C1236T, ABCB1C3435T, CYP3A5&z.ast;3, ABCG2 c.34G A, c.421C A, SLCO1B1 c.388A G, c.571T C and c.597C T. We conclude that CYP2C9&z.ast;3, ABCB1 G2677T/A, SLCO1B1 c.521T C, SLCO1B1 g.11187G A, SLCO1B1&z.ast;17 and gender contribute to inter-subject variability in pitavastatin pharmacokinetics. Personalized medicine should be necessary for hypercholesterolaemic patients receiving pitavastatin.