Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Germany.
Br J Clin Pharmacol. 2019 Oct;85(10):2310-2320. doi: 10.1111/bcp.14040. Epub 2019 Aug 9.
Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750 mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem.
We enrolled 12 healthy volunteers in a trial investigating the dose-exposure relationship of single ascending chlorzoxazone oral doses over a 10,000-fold range (0.05-500 mg) and assessed the effect of 0.1 and 500 mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003 mg).
Chlorzoxazone area under the concentration-time curve was dose-linear in the dose range between 0.05 and 5 mg. A nonlinear increase occurred with doses ≥50 mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration-time curve increased 2-fold when coadministered with 500 mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses.
The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.
氯唑沙宗是体内 CYP2E1 表型研究的典型标记物底物。由于在常用的毫克剂量（250-750mg）下，氯唑沙宗是 CYP3A4/5 标记物底物咪达唑仑的抑制剂，因此之前的尝试未能将这两种药物组合在一个共同的表型分析混合物中。氯唑沙宗微剂量可以规避这个问题。
我们招募了 12 名健康志愿者参与一项试验，研究单剂量氯唑沙宗口服剂量在 10000 倍范围内（0.05-500mg）的剂量-暴露关系，并评估了 0.1mg 和 500mg 氯唑沙宗对口服咪达唑仑药代动力学（0.003mg）的影响。
氯唑沙宗在 0.05-5mg 剂量范围内，药时曲线下面积呈剂量线性。当剂量≥50mg 时，出现非线性增加，可能是由于预体内代谢消除饱和所致。当与 500mg 氯唑沙宗合用时，咪达唑仑药时曲线下面积增加了 2 倍，但氯唑沙宗和咪达唑仑微剂量之间没有药代动力学相互作用。
氯唑沙宗微剂量与 CYP3A 标记物底物咪达唑仑无相互作用，可在表型分析混合物中同时给药。这种微剂量测定法现在已准备好进一步验证和测试，作为一种表型分析程序，评估 CYP2E1 的诱导和抑制对氯唑沙宗微剂量药代动力学的影响。
