汉族志愿者阿米替林代谢与异喹呱羟化代谢的关系

8名男性健康志愿者po阿米替林100 mg后,以阿米替林及其3种代谢物的血浓度曲线下面积(AUC_0~∞)计算阿米替林的脱甲基化代谢及羟基化代谢能力。结果提示个体间阿米替林及其3种代谢物的AUC差异很大。其中7名志愿者测定异喹呱羟化代谢表型,6例为异喹呱强代谢者,1例为弱代谢者。尿中异喹呱的羟化代谢率与阿米替林的羟基化代谢率、阿米替林和10-羟基阿米替林的AUC_0~∞呈显著相关。阿米替林总血浆清除率与异喹呱羟化代谢率呈弱相关。此结果表明阿米替林和异喹呱的羟化代谢可能由同一酶控制,阿米替林的羟基化代谢和脱甲基化代谢可能为两个独立的代谢途径。

RELATIONSHIP BETWEEN AMITRIPTYLINE METABOLISM AND POLYMORPHIC DEBRISOQUINE HYDROXYLATION IN NATIVE CHINESE VOLUNTEERS

The demethylation and hydroxylation of amitriptyline were calculated from the ratios between the area under concentration--time curve (AUC) of amitriptyline and its three metabolites in eight healthy Chinese volunteers after a single oral dose of 100 mg amitriptyline. Great interindividual differences in AUCs of amitriptyline and its metabolites were observed.HPLC method was used to determine the debrisoquine hydroxylation phenotype in seven out of the eight volunteers. Six subjects were found to be rapid and one slow debrisoquine hydroxylators. The ratio between debrisoquine and 4-hydroxydebrisoquine in urine correlated significantly with the rate of amitriptyline hydroxylation and the AUCs of amitriptyline and 10-hydroxyamitriptyline, but not with that of amitriptyline demethylation. There also was a weak correlation between total plasma clearance and the hydroxylation of debrisoquine. These data suggest that the hydroxylation of amitriptyline and debrisoquine may be regulated by similar enzymatic processes and the demethylation and hydroxylation processes in amitriptyline metabolism appear to undergo two separate pathways.