Pharmacy Department, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
National Institute for Drug Clinical Trial, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
J Clin Pharm Ther. 2020 Aug;45(4):632-637. doi: 10.1111/jcpt.13155. Epub 2020 May 7.
Nebivolol, a selective β1 adrenoreceptor antagonist, is predominantly metabolized by cytochrome P450 (CYP)2D6 and shows a wide interindividual variability in pharmacokinetics. The present study was conducted to evaluate the effects of the major CYP2D6 polymorphisms on nebivolol disposition in healthy Chinese volunteers.
Twenty-eight volunteers were enrolled and classified as CYP2D6*1/1, CYP2D61/10, CYP2D610/10 and CYP2D65 carriers according to their genotypes. The concentration of nebivolol was determined by high-performance liquid chromatography-tandem mass spectrometry. The association between the pharmacokinetic parameters and genotypes was evaluated using the unpaired t test or analysis of variance.
We evaluated the effects of CYP2D65 and 10 polymorphism on the pharmacokinetics of nebivolol. Plasma nebivolol peak concentration and area under the curve (AUC and AUC ) were significantly higher in subjects with CYP2D65 and CYP2D610/10 polymorphism than those in subjects with wild-type CYP2D6 (CYP2D61/1), whereas its plasma clearance was significantly lower in the CYP2D610/10 and CYP2D65 carriers. No significant differences in the peak time and terminal half-life of nebivolol were observed among CYP2D6*10/10, CYP2D61/1 and CYP2D65 carriers.
Both CYP2D6*5 and *10 polymorphism altered the pharmacokinetics of nebivolol in healthy Chinese volunteers. Further studies are required to investigate the effects of these single-nucleotide polymorphisms on the pharmacokinetics, pharmacodynamics and toxicity of nebivolol.
比索洛尔是一种选择性β1 肾上腺素受体拮抗剂，主要通过细胞色素 P450（CYP）2D6 代谢，其药代动力学在个体间存在广泛的变异性。本研究旨在评估主要 CYP2D6 多态性对健康中国志愿者比索洛尔处置的影响。
根据基因型将 28 名志愿者分为 CYP2D6*1/1、CYP2D61/10、CYP2D610/10 和 CYP2D65 携带者。比索洛尔的浓度采用高效液相色谱-串联质谱法测定。采用配对 t 检验或方差分析评估药代动力学参数与基因型之间的关系。
我们评估了 CYP2D65 和10 多态性对比索洛尔药代动力学的影响。与野生型 CYP2D6（CYP2D61/1）相比，CYP2D65 和 CYP2D610/10 多态性的受试者比索洛尔血浆峰浓度和曲线下面积（AUC 和 AUC）显著升高，而 CYP2D610/10 和 CYP2D65 携带者的比索洛尔血浆清除率显著降低。CYP2D6*10/10、CYP2D61/1 和 CYP2D65 携带者之间比索洛尔的达峰时间和半衰期无显著差异。
CYP2D65 和10 多态性改变了健康中国志愿者比索洛尔的药代动力学。需要进一步研究这些单核苷酸多态性对比索洛尔药代动力学、药效学和毒性的影响。
