【摘要】 目的 研究中国健康受试者细胞色素P450 2C9 （CYP2C9）及细胞色素P450 2C19（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AUC_0-t分别为（5 346.36±1 806.39）和（10 112.46±2 835.19）ng·mL^-1,C_max分别为（489.37±220.53）和（1 034.86±264.60）ng·mL^-1,t_max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，C_max和AUC_0-t差异均有统计学意义（均P<0.01）,t_max差异无统计学意义（P>0.05）。餐后组CYP2C9*3 AA和AC基因型的AUC_0-t分别为（7 496.90±2 625.10）和(9 941.29±2 073.53 ng·mL^-1,C_max分别为（1 289.61±410.86）和（1 501.06±55.05） ng·mL^-1,t_max分别为（4.12±1.19）和（4.50±5.95）h;CYP2C9*2 CC和CT基因型的AUC_0-t分别为（7 666.83±2 680.01）和7 287.80 ng·mL^-1,C_max分别为（1 304.11±407.37）和1 277.47 ng·mL^-1,t_max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。更多还原

【Abstract】 Objective To study the effect of cytochrome P450 2C9（CYP2C9） and cytochrome P450 2C19（CYP2C19） gene polymorphisms on the pharmacokinetics（PK） of celecoxib in healthy Chinese subjects.Methods A single-dose,two-formulation,two-period,twosequence,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 AUC_0-t of CYP2C9*3 AA and AC genotypes were（5 346.36±1 806.39） and（10 112.46±2 835.19） ng · mL^-1,respectively;the C_max were（489.37±220.53） and（1 034.86±264.60） ng · mL^-1,respectively;the t_max were（2.80±1.55） and（2.83±0.29） h,respectively.Compared with the AA genotype,there were significant differences in C_max and AUC_0-tin subjects with the AC genotype（both P <0.01）,but no significant difference in t_max（P> 0.05）.In fed group the AUC_0-t of CYP2C9^*3 AA and AC genotypes were（7 496.90±2 625.10） and（9 941.29±2 073.53） ng·mL^-1,respectively;the C_max were（1 289.61±410.86） and（1 501.06±55.05） ng · mL^-1,respectively;the t_max were（4.12±1.19） and（4.50±5.95） h,respectively;the AUC_0-t of CYP2C9^*2 CC and CT genotypes were（7 666.83±2 680.01） and 7 287.80 ng · mL^-1,respectively;the C_max were（1 304.11±407.37） and 1 277.47ng·mL^-1,respectively;the t_max 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 A A 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 should be fully considered to ensure the safety and efficacy of clinical medication when using celecoxib clinically.更多还原