Olesen O V, Linnet K
Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital in Aarthus, Aarthus University Hospital, Risskov, Denmark.
Drug Metab Dispos. 1997 Jun;25(6):740-4.
The metabolism of nortriptyline was studied in vitro using cDNA-expressed human cytochrome P450 isozymes 1A2, 3A4, 2C19, and 2D6, CYP2D6 was the sole isozyme mediating hydroxylation of nortriptyline, the quantitatively most important metabolic pathway, and only (E)-10-OH-nortriptyline was formed. CYP2D6, 2C19, and 1A2, mentioned in decreasing order of significance, mediated the demethylation reaction of nortriptyline, whereas 3A4 did not participate in the metabolism of nortriptyline. Concerning the quantitative relations, CYP2D6 exhibited a high affinity with respect to hydroxylation and demethylation (K(m) 0.48-0.74 mumol/l), a high hydroxylation capacity (Vmax 130 mol/hr/mol CYP) and a somewhat lower demethylation capacity (Vmax 19 mol/ hr/mol CYP). The affinities of 1A2 and 2C19 were 100-fold lower (K(m) 54-118 mumol/l). The capacity of 1A2 was low (Vmax 6.8 mol/hr/ mol CYP), whereas 2C19 had the highest demethylation capacity (Vmax 93 mol/hr/mol CYP). Taking into account the relative amounts of CYP isozymes present in the liver, about 90% of the metabolism was estimated to depend on CYP2D6, with CYP2C19 and 1A2 mediating the remaining 10%. In subjects lacking the 2D6 isozyme, CYP2C19 and 1A2 are expected to be of major importance for elimination of nortriptyline.
采用体外实验，利用互补脱氧核糖核酸（cDNA）表达的人细胞色素P450同工酶1A2、3A4、2C19和2D6研究了去甲替林的代谢。CYP2D6是介导去甲替林羟基化反应（这是定量上最重要的代谢途径）的唯一同工酶，且仅生成（E）-10-羟基去甲替林。按重要性递减顺序排列的CYP2D6、2C19和1A2介导了去甲替林的去甲基化反应，而3A4不参与去甲替林的代谢。关于定量关系，CYP2D6在羟基化和去甲基化方面表现出高亲和力（米氏常数K(m)为0.48 - 0.74微摩尔/升）、高羟基化能力（最大反应速度Vmax为130摩尔/小时/摩尔CYP）以及稍低的去甲基化能力（Vmax为19摩尔/小时/摩尔CYP）。1A2和2C19的亲和力低100倍（K(m)为54 - 118微摩尔/升）。1A2的能力低（Vmax为6.8摩尔/小时/摩尔CYP），而2C19具有最高的去甲基化能力（Vmax为93摩尔/小时/摩尔CYP）。考虑到肝脏中存在的CYP同工酶的相对含量，估计约90%的代谢依赖于CYP2D6，其余10%由CYP2C19和1A2介导。在缺乏2D6同工酶的受试者中，预计CYP2C19和1A2对去甲替林的消除起主要作用。
