Olesen O V, Linnet K
Department of Biological Psychiatry, Aarhus University Hospital, Risskov, Denmark.
Pharmacology. 1997 Nov;55(5):235-43. doi: 10.1159/000139533.
The metabolism of amitriptyline was studied in vitro using cDNA-expressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. CYP 2C19 was the most important enzyme with regard to the demethylation of amitriptyline, the quantitatively most important metabolic pathway. CYP 1A2, 3A4, 2C9 and CYP 2D6 also participated in the demethylation of amitriptyline. CYP 2D6 was the sole enzyme mediating the hydroxylation of amitriptyline, and (E)-10-OH-amitriptyline was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning the quantitative relations, CYP 2C19 and 2D6 exhibited high affinities with Km values in the range of 5-13 mumol/l, whereas the affinities of 1A2, 3A4 and 2C9 were somewhat lower with Km values ranging from 74 to 92 mumol/l. CYP 2C19 displayed the highest reaction capacity per mole with Vmax equal to 475 mol h-1 (mol CYP)-1. The other enzymes had Vmax values in the range of 90-145 mol h-1 (mol CYP)-1. Allowing for the typical relative distribution of amounts of CYP enzymes in the liver, a simulation study suggested that, at therapeutic doses, on average about 60% of the metabolism depended on CYP 2C19. At toxic doses, CYP 2C19 is expected to be saturated, and CYP 3A4 may now play a dominant role in the metabolism.
采用经cDNA表达的人细胞色素P450（CYP）酶1A2、3A4、2C9、2C19、2D6和2E1，在体外研究了阿米替林的代谢情况。就阿米替林的去甲基化而言，CYP 2C19是最重要的酶，而去甲基化是在数量上最为重要的代谢途径。CYP 1A2、3A4、2C9和CYP 2D6也参与了阿米替林的去甲基化过程。CYP 2D6是介导阿米替林羟基化的唯一酶，且仅生成（E）-10-羟基阿米替林。CYP 2E1不代谢阿米替林。关于定量关系，CYP 2C19和2D6表现出高亲和力，其米氏常数（Km）值在5 - 13 μmol/L范围内，而1A2、3A4和2C9的亲和力则稍低，Km值范围为74至92 μmol/L。CYP 2C19每摩尔的反应能力最高，其最大反应速度（Vmax）等于475 mol h-1（mol CYP）-1。其他酶的Vmax值在90 - 145 mol h-1（mol CYP）-1范围内。考虑到肝脏中CYP酶数量的典型相对分布情况，一项模拟研究表明，在治疗剂量下，平均约60%的代谢依赖于CYP 2C19。在中毒剂量下，预计CYP 2C19会饱和，此时CYP 3A4可能在代谢中起主导作用。
