Dreisbach A W, Ferencz N, Hopkins N E, Fuentes M G, Rege A B, George W J, Lertora J J
Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Clin Pharmacol Ther. 1995 Nov;58(5):498-505. doi: 10.1016/0009-9236(95)90169-8.
To determine whether the urinary excretion of 6-hydroxychlorzoxazone is an index of CYP2E1 activity in vivo.
Male volunteers (n = 27; age range, 17 to 36 years) who were abstinent from alcohol were studied. Chlorzoxazone, 500 mg, was given orally and plasma was collected at 31/2, 41/2, 51/2, and 61/2 hours after dosing. Urine was collected for 8 hours. Ten volunteers participated in full kinetic studies to define the absorption phase and plasma area under the concentration-time curve of chlorzoxazone and the urinary kinetics of the 6-hydroxy metabolite. Chlorzoxazone and the 6-hydroxy metabolite were measured by high-performance liquid chromatography. CYP2E1 activity was expressed as a hydroxylation index (HI = mmole oral chlorzoxazone dose/mmole 6-hydroxychlorzoxazone in 8-hour urine).
There was a significant positive correlation between plasma elimination rate constant for chlorzoxazone (Ke) and urinary excretion of the metabolite (n = 27, r = 0.42, p < 0.03) and a significant negative correlation between plasma Ke and HI (n = 27, r = -0.41, p < 0.04). The mean absorption rate constant for chlorzoxazone of 3.11 +/- 4.67 hr-1 was fivefold greater than the plasma Ke of 0.57 +/- 0.17 hr-1 for the full kinetic studies. The formation clearance of the 6-hydroxy metabolite was negative between plasma Ke of the parent compound and disposition rate constant for urinary excretion of the 6-hydroxy metabolite (n = 15, r = 0.85, p < 0.0001).
The urinary excretion of 6-hydroxychlorzoxazone is limited by formation rate and may be useful as an in vivo probe of CYP2E1 activity.
确定6 - 羟基氯唑沙宗的尿排泄量是否为体内CYP2E1活性的一个指标。
对27名戒酒的男性志愿者（年龄范围17至36岁）进行研究。口服500毫克氯唑沙宗，并在给药后3.5、4.5、5.5和6.5小时采集血浆。收集8小时尿液。10名志愿者参与完整的动力学研究，以确定氯唑沙宗的吸收阶段、浓度 - 时间曲线下的血浆面积以及6 - 羟基代谢物的尿动力学。通过高效液相色谱法测定氯唑沙宗和6 - 羟基代谢物。CYP2E1活性以羟化指数表示（HI = 口服氯唑沙宗剂量毫摩尔数/8小时尿液中6 - 羟基氯唑沙宗毫摩尔数）。
氯唑沙宗的血浆消除速率常数（Ke）与代谢物的尿排泄量之间存在显著正相关（n = 27，r = 0.42，p < 0.03），血浆Ke与HI之间存在显著负相关（n = 27，r = -0.41，p < 0.04）。在完整的动力学研究中，氯唑沙宗的平均吸收速率常数为3.11±4.67小时-1，比血浆Ke 0.57±0.17小时-1大五倍。母体化合物的血浆Ke与6 - 羟基代谢物的尿排泄处置速率常数之间，6 - 羟基代谢物的生成清除率为负相关（n = 15，r = 0.85，p < 0.0001）。
6 - 羟基氯唑沙宗的尿排泄受生成速率限制，可能作为CYP2E1活性的体内探针。
