The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.
The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.
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发表时间：
2000-04
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通讯作者：
JoAnn Hirth;P. Watkins;Myla H. Strawderman;A. Schott;R. Bruno;L. Baker
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作者：
JoAnn Hirth;P. Watkins;Myla H. Strawderman;A. Schott;R. Bruno;L. Baker
多西紫杉醇是一种治疗多种实体瘤的有效化疗药物。给予标准剂量多西他赛的患者在清除率（CL）和毒性作用方面表现出广泛的患者间差异。多西他赛通过细胞色素CYP3A4进行代谢。因此，患者之间CYP3A4活性的差异可能部分解释了毒性和CL的差异。21例重度预处理的转移性肉瘤患者接受多西他赛（100mg /m2）治疗。通过[14c - n -甲基]红霉素呼吸试验（ERMBT）检测每位患者的肝脏CYP3A4活性。在接下来的24小时内，在选定的时间采集血液样本进行药代动力学分析。ERMBT测定的肝脏CYP3A4活性的表型表达变化超过20倍（给予14C在1小时内呼出：平均，2.53%；范围，0.25-5.35%），与正常对照人群相似。多西他赛的CL变化近6倍（平均21.0升/h/m2，范围5.4-29.1升/h/m2）。与血清丙氨酸转氨酶、白蛋白、碱性磷酸酶或血清α -1-酸性糖蛋白相比，ERMBT是CL的最佳预测指标。ERMBT的自然对数占CL患者间差异的67%。多变量分析显示，ERMBT和白蛋白的自然对数共同占CL患者间变异的72%。最低ERMBT的患者毒性最大。肝脏CYP3A4活性是多西紫杉醇CL的最强预测因子，是CL患者间差异的主要原因。CYP3A4活性低的患者有CL降低的风险，因此可能会经历多西他赛增加的毒性。那些活跃度高的人可能接受的剂量不够理想。通过测量CYP3A4活性，ERMBT可能在临床上对某些个体的CYP3A4底物（如多西紫杉醇）的剂量定制有用。
Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.