Frye R F, Adedoyin A, Mauro K, Matzke G R, Branch R A
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15261, USA.
J Clin Pharmacol. 1998 Jan;38(1):82-9. doi: 10.1002/j.1552-4604.1998.tb04381.x.
Chlorzoxazone is being developed and proposed for use as a probe to measure in vivo cytochrome P4502E1 activity, but the phenotypic trait measures that are used vary. Although the doses proposed for phenotyping range from 250 mg to 750 mg, the effect of dose on chlorzoxazone hydroxylation has not previously been evaluated. The purpose of this study was to characterize the pharmacokinetics of chlorzoxazone in normal healthy volunteers (N = 6) after single randomized oral doses of 250 mg and 750 mg. An additional 10 volunteers underwent a detailed pharmacokinetic study using the 250-mg dose to further evaluate proposed phenotypic trait measures (N = 16). Timed blood and urine samples were obtained for 10 hours for chlorzoxazone and 6-hydroxychlorzoxazone determination by HPLC. Pharmacokinetic parameter estimates were estimated using noncompartmental methods. Evaluation of phenotypic trait measures show that 6-hydroxychlorzoxazone to chlorzoxazone plasma concentration ratios at 2 to 4 hours after drug administration demonstrated the highest correlations with metabolite formation clearance (r = 0.9; P < 0.001). Urine-based parameters (e.g., total recovery) were not significantly related to formation clearance (r = 0.5; P > 0.05). Dose dependency in chlorzoxazone metabolism was shown by a 30% increase (P < 0.05) in the dose-normalized area under the concentration-time curve (AUC) of chlorzoxazone and lower incremental dose-normalized urinary recovery of 6-hydroxychlorzoxazone at early timepoints after the 750-mg dose. In addition, the plasma ratio of 6-hydroxychlorzoxazone to chlorzoxazone at 4 hours was reduced by 48% in 5 of 6 subjects after the 750-mg dose (P > 0.05). These data suggest that 6-hydroxylation was saturated at the higher dose and illustrate the importance of dose selection in phenotyping. The results of this study indicate that a chlorzoxazone dose of 250 mg should be used and that a single plasma ratio obtained 2 to 4 hours after dosing is reflective of chlorzoxazone 6-hydroxylation and thus may serve as a cytochrome P4502E1 phenotypic trait measure.
氯唑沙宗正在被研发并被提议用作测量体内细胞色素P4502E1活性的探针，但所使用的表型特征测量方法各不相同。尽管提议用于表型分析的剂量范围为250毫克至750毫克，但之前尚未评估剂量对氯唑沙宗羟基化的影响。本研究的目的是在单次随机口服250毫克和750毫克剂量后，对正常健康志愿者（N = 6）体内氯唑沙宗的药代动力学进行特征描述。另外10名志愿者使用250毫克剂量进行了详细的药代动力学研究，以进一步评估提议的表型特征测量方法（N = 16）。通过高效液相色谱法在10小时内定时采集血液和尿液样本，用于测定氯唑沙宗和6 - 羟基氯唑沙宗。使用非房室模型方法估算药代动力学参数。对表型特征测量方法的评估表明，给药后2至4小时6 - 羟基氯唑沙宗与氯唑沙宗的血浆浓度比与代谢物生成清除率的相关性最高（r = 0.9；P < 0.001）。基于尿液的参数（如总回收率）与生成清除率无显著相关性（r = 0.5；P > 0.05）。氯唑沙宗代谢的剂量依赖性表现为，750毫克剂量后早期，氯唑沙宗浓度 - 时间曲线下剂量标准化面积（AUC）增加30%（P < 0.05），而6 - 羟基氯唑沙宗的剂量标准化尿液回收率降低。此外，750毫克剂量后，6名受试者中有5名在4小时时6 - 羟基氯唑沙宗与氯唑沙宗的血浆比值降低了48%（P > 0.05）。这些数据表明，较高剂量下6 - 羟基化达到饱和，说明了剂量选择在表型分析中的重要性。本研究结果表明，应使用250毫克的氯唑沙宗剂量，给药后2至4小时获得的单一血浆比值反映了氯唑沙宗的6 - 羟基化，因此可作为细胞色素P4502E1的表型特征测量指标。
