Influence of CYP2D65 and 10 polymorphism on the pharmacokinetics of nebivolol in healthy Chinese subjects

• Published in: Journal of clinical pharmacy and therapeutics Vol. 45; no. 4; pp. 632 - 637
• Main Authors: Guo, Lifang, Wang, Shumin, Wan, Zirui, Ni, Siyang, Xu, Benshan, Zhao, Xiuli, Liu, Lihong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2020
• Subjects: Adrenergic receptors; Adult; Area Under Curve; Asian Continental Ancestry Group - genetics; CYP2D6 protein; CYP2D610; CYP2D65; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P450; Female; Gene polymorphism; Genotype; Healthy Volunteers; Humans; Liquid chromatography; Male; Mass spectroscopy; nebivolol; Nebivolol - pharmacokinetics; Pharmacodynamics; Pharmacokinetics; Polymorphism; Polymorphism, Genetic - genetics; Toxicity; Young Adult; pharmacokinetics; nebivolol; CYP2D610; CYP2D65
• ISSN: 0269-4727; 1365-2710; 1365-2710
• DOI: 10.1111/jcpt.13155

What is known and objective 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. Methods Twenty‐eight volunteers were enrolled and classified as CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10 and CYP2D6*5 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. Results and discussion We evaluated the effects of CYP2D6*5 and *10 polymorphism on the pharmacokinetics of nebivolol. Plasma nebivolol peak concentration and area under the curve (AUC(0‐48 h) and AUC(0‐∞)) were significantly higher in subjects with CYP2D6*5 and CYP2D6*10/*10 polymorphism than those in subjects with wild‐type CYP2D6 (CYP2D6*1/*1), whereas its plasma clearance was significantly lower in the CYP2D6*10/*10 and CYP2D6*5 carriers. No significant differences in the peak time and terminal half‐life of nebivolol were observed among CYP2D6*10/*10, CYP2D6*1/*1 and CYP2D6*5 carriers. What is new and conclusion 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. Flow diagram for subject selection and nebivolol pharmacokinetic‐pharmacogenomic study.