Zhou Quan, Chen Qiu-Xia, Ruan Zou-Rong, Yuan Hong, Xu Hui-Min, Zeng Su
Department of Pharmacy, the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Pharmazie. 2013 Mar;68(3):187-94.
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 CYP2C91/1 carriers, CYP2C91/3 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-SLCO1B117 carriers, SLCO1B117 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, CYP3A53, ABCG2 c.34G > A, c.421C > A, SLCO1B1 c.388A>G, c.571T>C and c.597C>T. We conclude that CYP2C93, 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.
在12名中国志愿者中进行了一项药代动力学研究，采用单剂量1毫克、2毫克和4毫克的匹伐他汀钙，采用开放标签、随机、三期交叉设计。采用高效液相色谱法测定血浆中匹伐他汀酸和匹伐他汀内酯的浓度。采用TaqMan（MGB）基因分型法测定ABCB1、ABCG2、SLCO1B1、CYP2C9和CYP3A5中的单核苷酸多态性（SNP）。分析上述SNP与剂量标准化（基于1毫克）的血浆浓度-时间曲线外推至无穷大的面积[AUC(0-无穷大)]以及匹伐他汀酸和内酯形式的血浆峰浓度（Cmax）值之间的关系。匹伐他汀呈现线性药代动力学且个体间差异较大。与CYP2C91/1携带者相比，CYP2C91/3携带者的匹伐他汀酸的AUC(0-无穷大)和Cmax以及匹伐他汀内酯的AUC(0-无穷大)更高（P<0.05）。关于ABCB1 G2677T/A，与GT、GA或GG基因型携带者相比，非G携带者的匹伐他汀酸的Cmax和AUC(0-无穷大)以及匹伐他汀内酯的Cmax更高（P<0.05）。观察到SLCO1B1 c.521T>C和g.11187G>A对酸和内酯形式药代动力学的基因剂量效应。与非SLCO1B117携带者相比，SLCO1B117携带者的酸和内酯形式具有更高的Cmax和AUC(0-无穷大)（P<0.05）。观察到内酯药代动力学存在显著的性别差异。女性SLCO1B1 521TT受试者的匹伐他汀内酯的Cmax和AUC(0-无穷大)高于男性521TT受试者，然而，这种性别差异在521 TC和521CC受试者中消失。ABCB1 C1236T、ABCB1C3435T、CYP3A53、ABCG2 c.34G>A、c.421C>A、SLCO1B1 c.388A>G、c.571T>C和c.597C>T对匹伐他汀的药代动力学无显著影响。我们得出结论，CYP2C93、ABCB1 G2677T/A、SLCO1B1 c.521T>C、SLCO1B g.11187G>A、SLCO1B1*17和性别导致了匹伐他汀药代动力学的个体间差异。接受匹伐他汀治疗的高胆固醇血症患者应进行个性化用药。
