乳腺癌耐药蛋白BCRP基因多态性对瑞舒伐他汀人体药动学的影响  

Effects of breast cancer resistance protein(BCRP) polymorphism on rosuvastatin pharmacokinetics in Chinese healthy subjects

作　　者：田蕾[1] 韩璐璐[1] 蒋娟娟[1] 刘红[1] 严岩[1] 黄一玲[1] 李一石[1] 

机构地区：[1]中国医学科学院北京协和医学院暨阜外心血管病医院临床药理中心,卫生部心血管药物临床研究重点实验室,北京100037

出　　处：《中国新药杂志》2014年第1期62-66,共5页Chinese Journal of New Drugs

基　　金：国家"重大新药创制"科技重大专项(2012ZX09303008-001);2010年国家临床重点专科建设项目(卫生部重点实验室)

摘　　要：目的:比较研究BCRP基因多态性对瑞舒伐他汀单剂量和多剂量连续给药后人体药动学的影响。方法:筛选24例健康受试者,按BCRP 421 C>A基因型分组:421CC野生组(n=15)和421CA+AA突变组(n=9)。受试者每日口服规定剂量的瑞舒伐他汀,连续7 d;每日按规定时间点采集受试者血样和尿样;采用液相色谱-串联质谱联用法(HPLC-MS/MS)测定血浆和尿样中的瑞舒伐他汀浓度。结果:单剂量给药后,瑞舒伐他汀在BCRP 421CA+AA突变组的AUC0～t,C max和尿药排泄百分数Percent_excretion显著高于421CC野生型组(P=0.030,0.015和0.041),半衰期t1/2和达峰时间T max在两组人群中无差异(P>0.05)。与单剂量结果不同,多剂量连续给药达稳态后,稳态AUC ss,C max、总清除率CL total_ss/F和肾清除率CL R_ss在野生型组和突变组之间均无显著性差异(P>0.05),但半衰期t1/2在野生组显著延长[(14.1±3.1)vs(11.8±2.2)h,P=0.035],且野生组的蓄积比Rac也高于突变组(P=0.064)。结论:BCRP 421C>A基因多态性是影响瑞舒伐他汀人体药动学改变的重要因素。Objective： To assess the influence of breast cancer resistance protein （BCRP） polymorphism on the pharmacokinetics of rosuvastatin. Methods ： Twenty-four Chinese healthy male subjects were selected to par- ticipate in this study. Fifteen were carriers of 421CC wild-type BCRP, the others were carriers with at least one 421C 〉 A mutant allele （seven subjects had a genotype of 421CA and two were homozygotes of 421AA）. Each sub- ject was grouped randomly to receive 5, 10 or 20 mg rosuvastatin orally once a day for 7 days. The plasma and u- rine concentrations of rosuvastatin were determined by HPLC-MS/MS method. Results ： After single oral dose of ro- suvastatin, the AUC0~,, Cmax and percent of cumulative urine excretion amount （Percent_ex） were significantly higher in BCRP 421CA ＋AA group than those in the 421CC wild-type group （P = 0. 030, 0. 015 and 0. 041 , re- spectively） , whereas there was no difference in the tl/2 and Tmax between these groups. In contrast, no significant differences were found between the two genotype groups in terms of AUC~, C total clearance and renal clear-ance values at steady state （P that in 421CA ＋ AA group （P 〉0.05）, =0.035）. but a prolonged tl/2 was observed in 421CC wild-type group compared with Conclusion ： The BCRP 421C 〉 A variant is one of the determinant factors governing the interindividual variability in the pharmacokinetics of rosuvastatin

关 键 词：乳腺癌耐药蛋白 瑞舒伐他汀 基因多态性 药动学 

分 类 号：R978.15[医药卫生—药品] R969.1[医药卫生—药学]