Belpaire F M, Wijnant P, Temmerman A, Rasmussen B B, Brøsen K
Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.
Eur J Clin Pharmacol. 1998 May;54(3):261-4. doi: 10.1007/s002280050456.
Biotransformation of metoprolol to alpha-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) is mediated by CYP2D6. The selective serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6. The aim was to study in vitro the potential inhibitory effect of SSRIs on metoprolol biotransformation.
Using microsomes from two human livers, biotransformation of metoprolol to alpha-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) as a function of the concentrations of the SSRIs and of some of their metabolites was studied.
The kinetics of the formation of both metabolites are best described by a biphasic enzyme model. The estimated values of Vmax and kM for the high affinity site are for the alpha-hydroxylation in human liver HL-1 32 pmol mg(-1) min(-1) and 75 micromol x l(-1) respectively, and in human liver HL-9 39 pmol mg(-1) x min(-1) and 70 micromol x l(-1) respectively; for the O-demethylation in HL-1 131 pmol mg(-1) min(-1) and 95 micromol x l(-1) respectively, and in HL-9 145 pmol mg(-1) min(-1) and 94 micromol x l(-1) respectively. Quinidine is for both pathways a potent inhibitor of the high-affinity site, with K(i) values ranging from 0.03 to 0.18 micromol x l(-1). Fluoxetine, norfluoxetine and paroxetine are likewise potent inhibitors, with Ki values ranging from 0.30 to 2.1 micromol x l(-1) fluvoxamine, sertraline, desmethylsertraline, citalopram and desmethylcitalopram are less potent inhibitors, with K(i) values above 10 micromol x l(-1).
The rank order of the SSRIs for inhibition of metoprolol metabolism is comparable to that reported in the literature for other CYP2D6 substrates, with fluoxetine, norfluoxetine and paroxetine being the most potent. These findings need further investigation to determine their clinical relevance.
美托洛尔向α-羟基美托洛尔（HM）和O-去甲基美托洛尔（ODM）的生物转化由CYP2D6介导。已知选择性5-羟色胺再摄取抑制剂（SSRI）可抑制CYP2D6。本研究旨在体外研究SSRI对美托洛尔生物转化的潜在抑制作用。
使用来自两个人肝脏的微粒体，研究美托洛尔向α-羟基美托洛尔（HM）和O-去甲基美托洛尔（ODM）的生物转化与SSRI及其某些代谢产物浓度的关系。
两种代谢产物形成的动力学最好用双相酶模型描述。高亲和力位点的Vmax和kM估计值，对于人肝脏HL-1中的α-羟基化分别为32 pmol mg(-1) min(-1)和75 μmol x l(-1)，对于人肝脏HL-9中的α-羟基化分别为39 pmol mg(-1) x min(-1)和70 μmol x l(-1)；对于HL-1中的O-去甲基化分别为131 pmol mg(-1) min(-1)和95 μmol x l(-1)，对于HL-9中的O-去甲基化分别为145 pmol mg(-1) min(-1)和94 μmol x l(-1)。奎尼丁对两条途径都是高亲和力位点的强效抑制剂，K(i)值范围为0.03至0.18 μmol x l(-1)。氟西汀、去甲氟西汀和帕罗西汀同样是强效抑制剂，Ki值范围为0.30至2.1 μmol x l(-1)；氟伏沙明、舍曲林、去甲舍曲林、西酞普兰和去甲基西酞普兰是较弱的抑制剂，K(i)值高于10 μmol x l(-1)。
SSRI抑制美托洛尔代谢的强度顺序与文献中报道的其他CYP2D6底物的顺序相当，氟西汀、去甲氟西汀和帕罗西汀最强效。这些发现需要进一步研究以确定其临床相关性。
