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通过检测咖啡因及其代谢产物 ,探讨细胞色素P450 酶的亚型1A2(CYP1A2)在体内氯氮平去甲基代谢中的作用。9例男性健康志愿者口服单剂咖啡因150mg ,5h时采取血样和尿样 ,咖啡因代谢产物与咖啡因的比值反映CYP1A2活性。两天后单剂氯氮平10mg,收集0～24h尿和药代动力学设计的血样。0～24h尿中氯氮平剩余量占给药剂量的百分率(CLZ %dose)以及氯氮平0～24h药时曲线下面积(AUC0→24)可以反映氯氮平清除 ;0～24h尿中去甲氯氮平生成量占氯氮平给药剂量的百分率(DCLZ %dose)以及去甲氯氮平AUC0→24 可以反映去甲氯氮平生成。结果显示 ,血清咖啡因代谢比值(17X/137X)与尿中氯氮平清除率CLZ %dose(r= -0.2032,P>0.05)无显著相关 ,与尿中去甲氯氮平生成率DCLZ %dose(r=0.6824,P<0.05)正相关 ;血清咖啡因代谢比值还与氯氮平AUC0→24 的倒数(r=0.8098,P<0.01)以及去甲氯氮平AUC0→24 (r=0.7525,P<0.05)正相关。尿中咖啡因代谢比值[(17X +17U)/137X]与氯氮平AUC0→24的倒数(r=0.6982,P<0.05)以及去甲氯氮平AUC0→24(r=0.8480,P<0.01)正相关。本研究通过酶活性相关实验证实CYP1A2在体内氯氮平的清除及其去甲基代谢产物的生成上起作用。临床上合用其他影响CYP1A2活性的药物时需密切监测氯氮平血浓度。
By detecting caffeine and its metabolites, the role of cytochrome P450 enzyme subtype 1A2 (CYP1A2) in clozapine demethylation in vivo was explored. Nine healthy male volunteers were given a single dose of caffeine 150 mg orally and blood samples and urine samples were taken at 5 h. The ratio of caffeine metabolites to caffeine reflected CYP1A2 activity. Two days after a single dose of clozapine 10mg, collected 0 ~ 24h urine and pharmacokinetic design of blood samples. 0 ~ 24h urine clozapine dose (CLZ% dose) and clozapine 0 ~ 24h area under the curve (AUC0 → 24) can reflect the clozapine clearance; 0 ~ 24h urine Clozapine production to clozapine dose (DCLZ% dose), and norczapine AUC0 → 24 can be reflected in the generation of Clozapine. The results showed that the serum caffeine metabolism ratio (17X / 137X) was not significantly correlated with the CLZ% dose (r = -0.2032, P> 0.05) (r = 0.6824, P <0.05). The ratio of serum caffeine metabolism was also inversely correlated with the reciprocal of clozapine AUC0 → 24 (r = 0.8098, P <0.01) and the level of AUC0 → 24 , P <0.05). (R = 0.8480, P <0.01) in the urinary caffeine metabolism ratio [(17X + 17U) / 137X] and clozapine AUC0 → 24 (r = 0.6982, ) Is positive. In this study, we found that CYP1A2 plays a role in the clearance of clozapine and the production of its demethylated metabolites in vivo through enzyme activity-related experiments. Clinically combined with other drugs that affect the activity of CYP1A2 closely monitor clozapine concentration.