CYP2C9及CYP2C19基因多态性与塞来昔布健康受试者的药代动力学研究  

Influence of CYP2C9 and CYP2C19 gene polymorphism on the pharmacokinetics of single dose oral celecoxib in healthy Chinese subjects

作　　者：何旭[1,2] 解染[1] 周双 张晓丹[1] 赵彩芸[2] 吕媛[2] 崔一民[1,2,3] 赵侠[1] HE Xu;XIE Ran;ZHOU Shuang;ZHANG Xiao-dan;ZHAO Cai-yun;LÜYuan;CUI Yi-min;ZHAO Xia(Department of Pharmacy,Peking University First Hospital,Beijing 100034,China;Institute of Clinical Pharmacology,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China;Department of Pharmacy Administration and Clinical Pharmacy,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China)

机构地区：[1]北京大学第一医院药学部,北京100034 [2]北京大学临床药理研究所,北京100191 [3]北京大学药学院药学管理与临床药学,北京100191

出　　处：《中国临床药理学杂志》2023年第16期2373-2377,共5页The Chinese Journal of Clinical Pharmacology

基　　金：国家科技重大专项-重大新药创制课题资助项目(2017ZX09101001);医药创新品种研发培育及产业支撑平台能力建设课题资助项目(Z191100007619038);国家重点研发计划课题资助项目(2020YFC2008304)。

摘　　要：目的研究中国健康受试者细胞色素P4502C9(CYP2C9)及细胞色素P4502C19(CYP2C19)基因多态性对塞来昔布在体内药代动力学(PK)的影响。方法采用单剂量、两制剂、两周期、双序列、随机交叉试验设计。空腹和餐后试验均入组31例受试者,空腹或餐后条件下单次口服塞来昔布胶囊0.2 g,用液相色谱串联质谱方法测定塞来昔布血样浓度,计算主要PK参数。用一代测序(Sanger测序)法对CYP2C9、CYP2C19基因多态性位点进行检测分型,并分析塞来昔布在各基因型受试者体内代谢特征的差异。结果空腹组CYP2C9*3 AA和AC基因型的AUC0-t分别为(5346.36±1806.39)和(10112.46±2835.19)ng·mL^(-1),Cmax分别为(489.37±220.53)和(1034.86±264.60)ng·mL^(-1),tmax分别为(2.80±1.55)和(2.83±0.29)h。携带CYP2C9*3 AC基因型受试者与AA基因型比较,Cmax和AUC0-t差异均有统计学意义(均P<0.01),tmax差异无统计学意义(P>0.05)。餐后组CYP2C9*3 AA和AC基因型的AUC0-t分别为(7496.90±2625.10)和(9941.29±2073.53 ng·mL^(-1),Cmax分别为(1289.61±410.86)和(1501.06±55.05)ng·mL^(-1),tmax分别为(4.12±1.19)和(4.50±5.95)h;CYP2C9*2 CC和CT基因型的AUC0-t分别为(7666.83±2680.01)和7287.80 ng·mL^(-1),Cmax分别为(1304.11±407.37)和1277.47 ng·mL^(-1),tmax分别为(4.17±1.17)和3.5 h。携带CYP2C9*3 AC基因型受试者与AA基因型比较,携带CYP2C9*2 CT基因型受试者与CC基因型比较,主要PK参数均无统计学意义(均P>0.05)。结论CYP2C9基因多态性可能影响塞来昔布体内PK过程。在临床应用时,应充分考虑CYP2C9基因多态性的影响,保障临床用药的安全性和有效性。Objective To study the effect of cytochrome P4502C9(CYP2C9)and cytochrome P4502C19(CYP2C19)gene polymorphisms on the pharmacokinetics(PK)of celecoxib in healthy Chinese subjects.Methods A single-dose,two-formulation,two-period,two-sequence,randomized crossover trial was designed.Thirty-one subjects were enrolled in both fasting and fed states,and received a single oral dose of 0.2 g celecoxib capsule under either fasting or fed conditions.Liquid chromatography-tandem mass spectrometry was used to determine celecoxib blood concentrations and calculate major PK parameters.First-generation sequencing(Sanger sequencing)was used to detect and analyze CYP2C9 and CYP2C19 gene polymorphism sites,and differences in metabolic characteristics of celecoxib among genotypes were analyzed.Results In fasting group,the AUC0-t of CYP2C9*3 AA and AC genotypes were(5346.36±1806.39)and(10112.46±2835.19)ng·mL^(-1),respectively;the Cmax were(489.37±220.53)and(1034.86±264.60)ng·mL^(-1),respectively;the tmax were(2.80±1.55)and(2.83±0.29)h,respectively.Compared with the AA genotype,there were significant differences in Cmax and AUC0-t in subjects with the AC genotype(both P<0.01),but no significant difference in tmax(P>0.05).In fed group the AUC0-t of CYP2C9*3 AA and AC genotypes were(7496.90±2625.10)and(9941.29±2073.53)ng·mL^(-1),respectively;the Cmax were(1289.61±410.86)and(1501.06±55.05)ng·mL^(-1),respectively;the tmax were(4.12±1.19)and(4.50±5.95)h,respectively;the AUC0-t of CYP2C9*2 CC and CT genotypes were(7666.83±2680.01)and 7287.80 ng·mL^(-1),respectively;the Cmax were(1304.11±407.37)and 1277.47 ng·mL^(-1),respectively;the tmax were(4.17±1.17)and 3.5 h,respectively.There was no statistically significant difference in major PK parameters between subjects with the AC genotype compared with the AA genotype or between subjects with the CT genotype compared with the CC genotype(all P>0.05).Conclusion CYP2C9 gene polymorphism may affect the PK process of celecoxib in vivo.The influence of CYP2C9 gene polymorphism sh

关 键 词：塞来昔布 细胞色素P4502C9 血液浓度 药代动力学 基因多态性 

分 类 号：R97[医药卫生—药品]