Abstract：
To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug.
摘要：
为了研究携带CYP2D6基因型且代谢表型未知的志愿者的药代动力学和药效学特征，根据测序结果共招募了22名志愿者.在口服美托洛尔后的特定时间点收集外周血和尿液样品。使用经过验证的高效液相色谱（HPLC）方法确定美托洛尔和α-羟基美托洛尔的浓度。还监测血压和心电图。结果表明，美托洛尔在CYP2D6*1/*34载体中的主要药代动力学参数与CYP2D6*1/*1载体中的主要药代动力学参数相似。然而,在携带CYP2D6*10/*87，CYP2D6*10/*95和CYP2D6*97/*97基因型的个体中，与野生型相比，美托洛尔的曲线下面积（AUC）和半衰期（t1/2）增加了2-3倍。这些基因型中美托洛尔的尿代谢比率与血浆样品中观察到的趋势一致。因此,CYP2D6*1/*34可以被认为是正常的代谢者，而CYP2D6*10/*87、CYP2D6*10/*95和CYP2D6*97/*97是中间代谢者。尽管已发现美托洛尔的血药浓度与CYP2D6基因型相关，其降血压效果在降低25mmHg时达到最大效果。此外，P-Q间期延长和心率降低与美托洛尔血液暴露无正相关。基于药代动力学-药效学模型,本研究阐明了美托洛尔在具有新型CYP2D6基因型的受试者中的性质，并为该底物药物的转化医学提供了重要的基础数据。
