Kirchheiner Julia, Heesch Claudia, Bauer Steffen, Meisel Christian, Seringer Angela, Goldammer Mark, Tzvetkov Mladen, Meineke Ingolf, Roots Ivar, Brockmöller Jürgen
Institute of Clinical Pharmacology, Humboldt University, Berlin, Germany.
Clin Pharmacol Ther. 2004 Oct;76(4):302-12. doi: 10.1016/j.clpt.2004.07.002.
In the treatment of heart failure and hypertension with metoprolol, ultrarapid metabolizers (UMs) may not achieve optimal target concentrations with recommended doses. We compared metoprolol pharmacokinetics and effects in UMs with extensive metabolizers (EMs) and with poor metabolizers (PM) as an additional reference group.
After a single dose of 100 mg metoprolol, pharmacokinetics, resting and exercise heart rate, and blood pressure were analyzed in relation to the CYP2D6 genotypes. We included 12 UMs, 13 EMs, and 4 PMs (healthy volunteers). CYP2D6 genotyping covered alleles *1 to *6 , *9 , *10 , *35 , and *41 and the duplications. beta 1 -Adrenergic receptor polymorphisms Ser49Gly and Arg389Gly were included as factors possibly interfering with the pharmacokinetic-pharmacodynamic relationship of metoprolol.
Median total metoprolol clearance values were 31, 168, and 367 L/h and median maximum plasma concentrations were 260, 118, and 67 microg/L in PMs, EMs, and UMs, respectively ( P < .0001). At 6 hours after administration, metoprolol reduced the exercise heart rate by median values of 31, 21, and 18 beats/min in PMs, EMs, and UMs, respectively ( P = .01). Blood pressure did not significantly differ according to CYP2D6 .
A linear relationship between the number of active CYP2D6 genes and metabolic clearance of metoprolol was found and the the median clearances differed by more than 10-fold between the PM and the UM groups. Metoprolol pharmacodynamics, however, differed only by less than 2-fold, and there was only a marginal difference in metoprolol efficacy on heart rate between the EM and UM groups.
在使用美托洛尔治疗心力衰竭和高血压时，超快代谢者（UMs）使用推荐剂量可能无法达到最佳目标浓度。我们将超快代谢者的美托洛尔药代动力学和效应与广泛代谢者（EMs）进行比较，并将慢代谢者（PMs）作为额外的参照组。
单次服用100mg美托洛尔后，分析药代动力学、静息心率和运动心率以及血压与CYP2D6基因分型的关系。我们纳入了12名超快代谢者、13名广泛代谢者和4名慢代谢者（健康志愿者）。CYP2D6基因分型涵盖了1至6、*9、*10、35和41等位基因以及重复序列。β1-肾上腺素能受体多态性Ser49Gly和Arg389Gly被纳入作为可能干扰美托洛尔药代动力学-药效学关系的因素。
慢代谢者、广泛代谢者和超快代谢者的美托洛尔总清除率中位数分别为31、168和367L/h，最大血浆浓度中位数分别为260、118和67μg/L（P<.0001）。给药后6小时，美托洛尔使慢代谢者、广泛代谢者和超快代谢者的运动心率分别降低了中位数31、21和18次/分钟（P=.01）。血压根据CYP2D6无显著差异。
发现活性CYP2D6基因数量与美托洛尔代谢清除率之间存在线性关系，慢代谢组和超快代谢组的中位数清除率相差超过10倍。然而，美托洛尔的药效学差异仅不到2倍，广泛代谢组和超快代谢组之间美托洛尔对心率的疗效仅存在微小差异。
