Soria-Chacartegui Paula, Zubiaur Pablo, Ochoa Dolores, Villapalos-García Gonzalo, Román Manuel, Matas Miriam, Figueiredo-Tor Laura, Mejía-Abril Gina, Calleja Sofía, de Miguel Alejandro, Navares-Gómez Marcos, Martín-Vilchez Samuel, Abad-Santos Francisco
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain.
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Research Institute, Kansas City, MO 64102, USA.
Pharmaceutics. 2023 Jan 25;15(2):404. doi: 10.3390/pharmaceutics15020404.
Amlodipine is an antihypertensive drug with unknown pharmacogenetic biomarkers. This research is a candidate gene study that looked for associations between amlodipine pharmacokinetics and safety and pharmacogenes. Pharmacokinetic and safety data were taken from 160 volunteers from eight bioequivalence trials. In the exploratory step, 70 volunteers were genotyped for 44 polymorphisms in different pharmacogenes. CYP2D6 poor metabolizers (PMs) showed higher half-life (t) (univariate -value () = 0.039, multivariate -value () = 0.013, β = -5.31, R = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC/DW) ( = 0.025; = 0.026, β = 578.90, R = 0.060) compared to the G/G genotype. In the confirmatory step, the cohort was increased to 160 volunteers, who were genotyped for , and . In addition to the previous associations, CYP2D6 UMs showed a lower AUC/DW ( = 0.046, = 0.049, β = -68.80, R = 0.073) compared to NMs, IMs and PMs and the rs34059508 G/A genotype was associated with thoracic pain ( = 0.038) and dizziness ( = 0.038, = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and and . Further research is needed to gather more evidence before its application in clinical practice.
氨氯地平是一种尚无已知药物遗传学生物标志物的抗高血压药物。本研究是一项候选基因研究，旨在探寻氨氯地平的药代动力学、安全性与药物基因之间的关联。药代动力学和安全性数据取自八项生物等效性试验的160名志愿者。在探索性阶段，对70名志愿者的不同药物基因中的44种多态性进行了基因分型。与超快代谢者（UMs）、正常代谢者（NMs）和中间代谢者（IMs）相比，CYP2D6慢代谢者（PMs）的半衰期（t）更长（单变量P值（P）=0.039，多变量P值（P）=0.013，β=-5.31，R=0.176）。与G/G基因型相比，rs34059508 G/A基因型与更高的剂量/体重校正曲线下面积（AUC/DW）相关（P=0.025；P=0.026，β=578.90，R=0.060）。在验证性阶段，队列扩大至160名志愿者，对其进行了[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]的基因分型。除了之前的关联外，与NMs、IMs和PMs相比，CYP2D6 UMs的AUC/DW更低（P=0.046，P=0.049，β=-68.80，R=0.073），且rs34059508 G/A基因型与胸痛（P=0.038）和头晕（P=0.038，P=0.014，log OR=10.975）相关。据我们所知，这是首次报道氨氯地平与[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]之间存在密切关系的研究。在其应用于临床实践之前，还需要进一步研究以收集更多证据。
