细胞色素P4502D6*10基因多态性对单次及多次口服奈必洛尔药代动力学的影响

Effect of cytochrome P450 2D6* 10 polymorphism on the pharmacokinetics of oral nebivolol after single and multiple doses

目的评价细胞色素P4502D6*10(CYP2D6*10)基因多态性对单次及多次口服奈必洛尔药代动力学的影响。方法根据CYP2D6*10基因型选择入选15名中国健康受试者,其中CYP2D6*1携带者8名,CYP2D6*10/*10基因型7名。所有受试者单次口服奈必洛尔5 mg和多次口服奈必洛尔5 mg·d-1,qd,连续7 d。用LC-MS/MS法测定奈必洛尔血药浓度,用Win Nonlin软件计算主要的药代动力学参数。结果单次口服奈必洛尔后CYP2D6*1携带者和CYP2D6*10/*10基因型个体中奈必洛尔的主要药代动力学参数:t1/2分别为(9.88±5.47),(12.29±6.19)h;AUCinf分别为(7.26±5.88),(8.56±5.20)μg·L-1·h;Cmax分别为(1.11±0.53),(1.42±0.75)μg·L-1。多次口服奈必洛尔后CYP2D6*1携带者和CYP2D6*10/*10基因型个体中奈必洛尔的主要药代动力学参数:t1/2分别为(8.56±2.38),(7.67±4.75)h;AUCinf分别为(10.62±5.62),(12.74±7.40)μg·L-1·h;Cmax分别为(2.05±0.83),(2.02±0.75)μg·L-1。奈必洛尔主要药代动力学参数在不同基因型组间比较差异无统计学意义(P>0.05)。多次给药的清除率在不同基因型中均显著低于单次给药(P<0.05)。结论 CYP2D6*10基因多态性对单次及多次口服奈必洛尔药代动力学无显著影响。多次给药后奈必洛尔体内消除减慢,且不受CYP2D6*10基因多态性影响。

Objective To evaluate the effect of cytochrome P450 2 D6＊10 （ CYP2 D6＊10 ） polymorphism on the pharmacokinetics of oral nebivolol after single and multiple doses. Methods Fifteen healthy volunteers which were selected according to their CYP2D6＊10 genotype, consisted of 8 of CYP2D6＊1 carriers and 7 of CYP2D6＊10/＊10 geno-types.All subjects received a single dose of 5 mg and multiple doses （5 mg· d-1 , qd, for 7 days） .Nebivolol in plasma were measured by LC-MS/MS.The main pharmacokinetic parameters were calculated by WinNonlin program.Results The main pharmacokinetic parameters of nebivolol in plasma between CYP2D6＊1 carriers and CYP2D6＊10/＊10 genotypes after a single dose were as follows： t1/2 were （9.88 ±5.47）, （ 12.29 ±6.19 ） h, AUCinf were （ 7.26 ±5.88 ）, （8.56 ±5.20）μg· L-1· h, Cmax were （1.11 ±0.53）, （1.42 ±0.75）μg· L-1 , respectively.The main pharmacokinetic parameters of nebivolol＆amp;nbsp;in plasma between CYP2D6＊1 carriers and CYP2D6＊10/＊10 genotypes after multiple doses were as follows：t1/2 were （8.56 ±2.38）, （7.67 ±4.75） h, AUCinf were （10.62 ±5.62）, （12.74 ±7.40）μg· L-1· h, Cmax were （2.05 ±0.83）, （2.02 ±0.75）μg· L-1, respectively.No significant differences in the pharmacokinetic parameters of nebivolol were found between CYP2D6＊1 carriers and CYP2D6＊10/＊10 genotypes.The clearance of the multiple doses was significantly lower compared with that of single dose in the different genotyped groups.Conclusion CYP2D6＊10 polymorphism has no significant effect on the pharmacokinetics of oral nebivolol after single and multiple doses.The elimination of nebivolol decreases after the multiple doses, which is not affected by CYP2D6＊10 polymorphism.