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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 effects of the CYP2D6 * 10 gene polymorphism on the pharmacokinetics of single and multiple oral doses of nebivolol. Methods Fifteen Chinese healthy subjects were selected according to the CYP2D6 * 10 genotype, including 8 CYP2D6 * 1 carriers and 7 CYP2D6 * 10 / * 10 genotypes. All subjects were treated with 5 mg nebivolol orally once a day and 5 mg · d-1, qd orally once daily for 7 days. The nebivolol plasma concentration was determined by LC-MS / MS and the main pharmacokinetic parameters were calculated by Win Nonlin software. Results The main pharmacokinetic parameters of Nebivolol in CYP2D6 * 1 carriers and CYP2D6 * 10 / * 10 individuals after single oral administration were: t1 / 2 = (9.88 ± 5.47), (12.29 ± 6.19) h and AUCinf were (7.26 ± 5.88) and (8.56 ± 5.20) μg · L-1 · h, respectively; Cmax was (1.11 ± 0.53) and (1.42 ± 0.75) μg · L-1, respectively. The main pharmacokinetic parameters of Nebivolol in CYP2D6 * 1 carriers and CYP2D6 * 10 / * 10 genotypes after repeated oral administration of nebivolol: t1 / 2 were (8.56 ± 2.38), (7.67 ± 4.75 ) h and AUCinf were (10.62 ± 5.62) and (12.74 ± 7.40) μg · L-1 · h, respectively; Cmax was 2.05 ± 0.83 and 2.02 ± 0.75 μg · L-1, respectively. Nepaleseol main pharmacokinetic parameters in different genotypes were no significant difference (P> 0.05). The clearance rate of multiple administrations was significantly lower than that of single administration in different genotypes (P <0.05). Conclusion The polymorphism of CYP2D6 * 10 has no significant effect on the pharmacokinetics of single and multiple oral doses of. Nebivolol elimination slowed down after multiple administrations and was not affected by CYP2D6 * 10 gene polymorphism.