ABCG2 34G>A和421C>A纯合子或复合杂合子的健康中国人体内瑞舒伐他汀药代动力学的显著改变
Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote.
作者信息
Wan Zirui, Wang Guo, Li Tailin, Xu Biaobo, Pei Qi, Peng Yan, Sun Hong, Cheng Lijuan, Zeng Ying, Yang Guoping, Zhu Yuan-Shan
机构信息
Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.)
出版信息
J Pharmacol Exp Ther. 2015 Sep;354(3):310-5. doi: 10.1124/jpet.115.225045. Epub 2015 Jun 16.
Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor used to lower blood low-density lipoprotein cholesterol, is a substrate of the membrane ABCG2 exporter. ABCG2 variants have been shown to alter rosuvastatin disposition. The objective of this study is to determine the impact of ABCG2 34/421 compound haplotypes on rosuvastatin pharmacokinetics in healthy Chinese volunteer subjects. Eight hundred healthy Chinese males were genotyped by polymerase chain reaction-pyrosequencing for ABCG2 34G>A, ABCG2 421C>A, SLCO1B1 521T>C, and CYP2C93 variants. Sixty-two male subjects with wild-type SLCO1B1 c.521TT and CYP2C93 were recruited for this pharmacokinetic study of rosuvastatin. A single oral dose of 10 mg rosuvastatin was administrated to each subject, and blood samples were collected before and at various time points after drug administration. Plasma concentration of rosuvastatin was determined by high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was carried out using the WinNonlin program. In Chinese males, high allele frequency of ABCG2 c.34G>A (0.275) and c.421C>A (0.282) was observed, resulting in a considerable portion (23.3%) of subjects being ABCG2 34/421 compound heterozygotes. Compared with subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin Cmax and area under the curve, AUC0-∞, were significantly higher, while the apparent oral clearance, CL/F, was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/421CA genotypes. Both t1/2 and Tmax were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G>A and c.421C>A variants was present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. These data suggest that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual.
瑞舒伐他汀是一种用于降低血液低密度脂蛋白胆固醇的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，是膜转运蛋白ABCG2的底物。已有研究表明，ABCG2基因变异会改变瑞舒伐他汀的代谢。本研究的目的是确定ABCG2 34/421复合单倍型对健康中国志愿者受试者中瑞舒伐他汀药代动力学的影响。采用聚合酶链反应-焦磷酸测序法对800名健康中国男性进行ABCG2 34G>A、ABCG2 421C>A、有机阴离子转运多肽1B1（SLCO1B1）521T>C和细胞色素P450 2C9（CYP2C9）3基因变异的基因分型。招募了62名SLCO1B1基因c.521位点为野生型TT且无CYP2C93变异的男性受试者进行瑞舒伐他汀的药代动力学研究。给每位受试者单次口服10 mg瑞舒伐他汀，并在给药前及给药后的不同时间点采集血样。采用高效液相色谱-串联质谱法测定瑞舒伐他汀的血浆浓度，并使用WinNonlin程序进行药代动力学分析。在中国男性中，观察到ABCG2基因c.34G>A（0.275）和c.421C>A（0.282）的等位基因频率较高，导致相当一部分（23.3%）受试者为ABCG2 34/421复合杂合子。与ABCG2野生型（c.34GG/421CC）受试者相比，c.34AA、c.421AA和c.34GA/421CA基因型受试者的血浆瑞舒伐他汀Cmax和曲线下面积（AUC0-∞）显著升高，而表观口服清除率（CL/F）显著降低。不同基因型受试者的t1/2和Tmax相似。中国男性中ABCG2基因c.34G>A和c.421C>A变异的频率较高，且这两种变异均显著影响瑞舒伐他汀的代谢。这些数据表明，在中国受试者中开具瑞舒伐他汀处方时，对这些变异进行基因分型是可取的，可为每个个体确定精确的剂量。
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