Koytchev R, Alken R G, Vlahov V, Kirkov V, Kaneva R, Thyroff-Friesinger U, Rehak E
Co-operative Clinical Drug Research and Development, Berlin, Germany.
Eur J Clin Pharmacol. 1998 Aug;54(6):469-74. doi: 10.1007/s002280050495.
The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D61/CYP2D61) and heterozygous (CYP2D61/CYP2D64) Caucasians.
Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D63 and CYP2D64) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared. Each formulation contained 200 mg metoprolol tartrate/(tablet). In each of the three periods of the trial, one of the formulations was administered under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the last dose and in selected time intervals thereafter. A sensitive and specific high-performance liquid chromatography (HPLC) method with fluorescence detection was applied for the quantification of metoprolol. Pharmacokinetic parameters were determined for each subject and statistically compared in two groups of 16 homozygous (CYP2D61/CYP2D61) and six heterozygous (CYP2D61/CYP2D64) volunteers.
Significant differences between homozygous and heterozygous individuals were observed for all pharmacokinetic parameters. The AUC in the course of one those interval of 24 h (AUCtau), minium steady-state concentration (C(min)ss) and average steady-state concentration (C(av)ss) values for heterozygous individuals were more than twice those of individuals. Significantly higher values for C(max)ss, t1/2, half-value duration (HVD) and mean residence time (MRT) were also observed in heterozygous volunteers. The higher concentrations of metoprolol in heterozygous individuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction.
本文旨在比较野生型CYP2D6等位基因（CYP2D61/CYP2D61）的纯合子白种人志愿者与杂合子（CYP2D61/CYP2D64）白种人中美托洛尔的药代动力学。
使用聚合酶链反应（PCR）对36名无关的健康男性白种人进行两种最常见突变等位基因（CYP2D63和CYP2D64）的筛查。24名基因型提示为快速羟化酶表型的志愿者参加了生物等效性试验，每人以随机、交叉方式接受三种比较制剂中的一种。每种制剂含200mg酒石酸美托洛尔/（片）。在试验的三个阶段中，每个阶段均在早晨空腹条件下连续4天给予其中一种制剂。在最后一剂前即刻及之后的选定时间间隔采集用于美托洛尔定量的血样。采用一种灵敏且特异的带荧光检测的高效液相色谱（HPLC）方法对美托洛尔进行定量。为每名受试者测定药代动力学参数，并在两组16名纯合子（CYP2D61/CYP2D61）和6名杂合子（CYP2D61/CYP2D64）志愿者中进行统计学比较。
在所有药代动力学参数方面，观察到纯合子与杂合子个体之间存在显著差异。杂合子个体在24小时的一个时间段（AUCtau）内的曲线下面积、最低稳态浓度（C(min)ss）和平均稳态浓度（C(av)ss）值是纯合子个体的两倍多。在杂合子志愿者中还观察到C(max)ss、t1/2、半值持续时间（HVD）和平均驻留时间（MRT）的值显著更高。杂合子个体中美托洛尔浓度较高也产生了药效学后果，即心率和血压降低幅度更大。
