Boulton D W, Arnaud P, DeVane C L
Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioural Sciences and Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA.
Br J Clin Pharmacol. 2001 Apr;51(4):350-4. doi: 10.1046/j.1365-2125.2001.01360.x.
To examine the effect of a single oral dose of methadone on cytochrome P450 (CYP) 3A activity using the urinary 6beta-hydroxycortisol to cortisol ratio (UCR) as a marker of CYP3A activity.
A single oral dose (0.2 mg kg-1) of rac-methadone was administered to eight healthy female volunteers. Frequent blood samples and all urine over seven time periods was collected for 96 h following dosing. The UCR and the concentration of the major CYP3A metabolite of methadone, EDDP, were measured in urine. Methadone enantiomer concentrations were determined in plasma and urine. All quantifications were performed by validated high performance liquid chromatography assays.
In all volunteers a significant decline of the UCR from immediately predose values was observed at the 4-8 and 8-12 h collection periods (P < 0.05, 95% CI for the differences: 0.4,16 and 0.6,16, respectively) with a return to immediately predose values after 2-3 days, suggesting methadone was an inhibitor of CYP3A. The UCR was found to be significantly correlated with the amount of EDDP excreted in the urine and with the area under the plasma concentration vs time profile for total (R + S) methadone, supporting in vitro data that CYP3A is primarily responsible for EDDP formation and has a significant influence on methadone disposition.
Methadone appears to be a CYP3A inhibitor in vivo following a single oral dose and measurements of the urinary cortisol ratio appear to be a useful index to follow this inhibition.
以尿中6β-羟基皮质醇与皮质醇比值（UCR）作为细胞色素P450（CYP）3A活性的标志物，研究单次口服美沙酮对CYP3A活性的影响。
对8名健康女性志愿者单次口服消旋美沙酮（0.2mg/kg）。给药后96小时内，在7个时间段频繁采集血样和全部尿液。测定尿液中的UCR和美沙酮主要CYP3A代谢产物EDDP的浓度。测定血浆和尿液中美沙酮对映体的浓度。所有定量分析均通过经过验证的高效液相色谱法进行。
在所有志愿者中，在4 - 8小时和8 - 12小时采集时间段观察到UCR较给药前即刻值显著下降（P < 0.05，差异的95%置信区间分别为0.4,16和0.6,16），2 - 3天后恢复到给药前即刻值，提示美沙酮是CYP3A的抑制剂。发现UCR与尿中排泄的EDDP量以及总（R + S）美沙酮的血浆浓度-时间曲线下面积显著相关，支持体外数据表明CYP3A主要负责EDDP的形成并对美沙酮处置有显著影响。
单次口服美沙酮后，美沙酮在体内似乎是一种CYP3A抑制剂，尿皮质醇比值的测定似乎是跟踪这种抑制作用的有用指标。
