Metabolism of tricyclic antidepressants and probe drug in treatment-resistant depressive patients.

本研究的目的是研究三环类抗抑郁药物和探针药物的代谢，探索难治性抑郁症的生物学背景。我们测定了73例接受阿米替林治疗的日本精神病患者血浆中阿米替林及其代谢物、去甲替林及其几何异构体10-羟基去甲替林和10-羟基阿米替林的浓度。尽管血浆药物浓度存在很大的个体差异，但药物浓度与阿米替林的日剂量之间存在显著的正相关。对49例抑郁症患者监测血浆阿米替林及其代谢产物水平对预测抑郁发作的临床意义进行了探讨。药物浓度和临床结果的判别分析显示，…血浆阿米替林和羟化代谢物的胞聚体水平的升高预示着较好的临床结果，而去甲替林和羟化代谢物的反式异构体的血浆水平的升高则预示着较差的临床结局，大约73%的受试者可以正确预测临床结局。日本患者的平均C浓度与日剂量之比是瑞典患者的2倍以上。日语中C的口腔清晰度仅为瑞典人的40%左右。这些发现表明，与瑞典人相比，日本人对叔胺三环类抗抑郁药的清除量更低。三胺类抗抑郁药脱甲基化的种族差异可能是由于日本人的细胞色素P450(CYP)同工酶CYP1A2和/或CYP2C19活性低于瑞典人所致。较少

The aim of this research project is investigating the metabolism of tricyclic antidepressants and probe drug and exploring the biological background of treatment-resistant depression. We measured the concentration in plasma of amitriptyline and its metabolites, nortriptyline and geometric isomers of 10 hydroxynortriptyline and 10-hydroxyamitriptyline in 73 Japanese psychiatric patients receiving amitriptyline. Although there were large interindividual variations in plasma drug concentrations, significant positive correlations were observed between drug concentrations and daily dose of amitriptyline. The metabolic ratios for both hydroxylation and desmethylation varied with 8-to 19 fold interindividual variations.The clinical significance of monitoring the plasma levels of amitriptyline and its metabolites in prediction of the clinical outcome of depressive episode was investigated in 49 depressive patients. Discriminant analysis of drug concentrations and clinical outcome revealed that … More increasing of the plasma levels of amitriptyline and cisisomers of hydroxylated metabolites predicted a better clinical outcome, while increasing of the plasma levels of nortriptyline and trans-isomers of hydroxylated metabolites were shown to predict a poor clinical outcome and clinical outcome of approximately 73% of the subjects could be correctly predicted.Interethnic differences in plasma concentrations of clomipramine between Japanese and Swedish patients was investigated using therapeutic drug monitoring data. The mean ratio between concentration of C and daily dose in Japanese patients was more than 2 times higher than that of Swedish patients. Oral clearance of C in Japanese was as low as approximately 40% of that of Swedes. These findings suggest that Japanese have a lower clearance of tertiary amine tricyclic antidepressants than Swedes do. Interethnic differences in desmethylation of tertiary amine tricyclic antidepressants might be caused by a lower activity of the cytochrome P450 (CYP) isozymes CYP1A2 and/or CYP2C19 in Japanese compared to Swedes. Less