Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment
Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment
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DOI：
10.1097/00008571-200208000-00007
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发表时间：
2002-08-01
期刊：
影响因子：
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通讯作者：
Eschenhagen, T
中科院分区：
文献类型：
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作者：
Rau, T;Heide, R;Eschenhagen, T
β（1）选择性β受体阻滞剂美托洛尔主要但不完全通过CYP 2D 6代谢。由于CYP 2D 6基因的多态性，CYP 2D 6活性在个体之间存在显著差异。因此，短期给药后，发现慢代谢型患者的美托洛尔血浆浓度比快代谢型患者高数倍。然而，目前尚不清楚CYP 2D 6多态性的影响是否在长期治疗期间持续存在，因为替代的消除或代谢机制可能在这种情况下有效。该研究包括91名长期接受美托洛尔治疗的白人患者（中位治疗持续时间为12.6个月;中位每日药物剂量：47.5 mg/天）。采用HPLC法测定美托洛尔和α-OH-美托洛尔的血浆浓度。基因分型检测到无效等位基因（*0）：*3、*4、*5、*6、*7、*8、*12、*14、*15，与酶活性降低相关的等位基因 *9、*10和 *41以及全功能等位基因 *1和 *2。基因型和等位基因频率与公布的频率为德国人口。基因型对血浆美托洛尔/α-CH-美托洛尔代谢率有显著影响（P< 0.0001）。相应地，*0/*0基因型患者（n = 8）和中间基因型患者（n = 10）的校正美托洛尔血浆浓度中位数分别是两个完全功能等位基因患者的6.2倍和3.9倍（n = 31; P< 0.01）。总之，CYP 2D 6基因型的显著影响在长期治疗期间持续存在，影响代谢率和美托洛尔血浆浓度。
The beta(1) selective beta-blocker metoprolol is metabolized predominantly but not exclusively by CYP2D6. Due to the polymorphism of the CYP2D6 gene, CYP2D6 activity varies markedly between individuals. Consequently, after short-term administration metoprolol plasma concentrations were found to be several fold higher in poor metabolizers than in extensive metabolizers. However, it is currently not known, whether the impact of the CYP2D6 polymorphism persists during long-term therapy, since alternate mechanisms of elimination or metabolism could be effective in this setting. The study comprised 91 Caucasian patients on long-term treatment with metoprolol (median duration of treatment 12.6 months; median daily drug dose: 47.5 mg/day). Metoprolol and alpha-OH-metoprolol plasma concentrations were assessed by HPLC. Genotyping detected the null alleles (*0): *3, *4, *5, *6, *7, *8, *12, *14, *15, the alleles *9, *10 and *41 associated with reduced enzymatic activity as well as the fully functional alleles *1 and *2. Genotype and allele frequencies were in accordance with published frequencies for the German population. The plasma metabolic ratio of metoprolol/alpha-CH-metoprolol was markedly affected by the genotype (P< 0.0001). In accordance, median adjusted metoprolol plasma concentrations were 6.2- and 3.9-fold higher in patients with *0/*0 genotypes (n = 8) and intermediate genotypes (n = 10), respectively, as compared to those with two fully functional alleles (n = 31; P< 0.01). In summary, the pronounced effect of the CYP2D6 genotype persists during long-term therapy, affecting both metabolic ratio and metoprolol plasma concentration.