Dexamethasone as a probe for docetaxel clearance
Dexamethasone as a probe for docetaxel clearance
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DOI：
10.1007/s00280-004-0823-0
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发表时间：
2004-09-01
影响因子：
3
通讯作者：
Roché, H
中科院分区：
文献类型：
--
作者：
Puisset, F;Chatelut, E;Roché, H
目的。为了评估多西他赛清除率（CL）与地塞米松药代动力学的相关性，在23例患者中进行了一项初步研究。地塞米松主要被CYP3A4羟基化，经常作为标准的多西他赛前用药。对已知CYP3A5 （G22893A）和mdr-1 （G2677T、G2677A和C3435T）的功能单核苷酸多态性（SNP）进行基因分型，以初步确定基因型与多西他赛和地塞米松药代动力学的相关性。患者和方法。为了符合这项研究的资格，患者必须患有多西他赛适应症的实体恶性肿瘤。采用群体药代动力学方法，通过贝叶斯分析确定多西他赛和地塞米松的个体药代动力学参数，筛选多西他赛CL与患者人口统计学、表型和基因型协变量之间的关系。结果。地塞米松的3个不同药动学参数与多西他赛CL有显著相关：地塞米松血浆清除率（DPC）在7.7 ~ 27.2 l/h之间，6 -羟地塞米松尿量，6 -羟地塞米松尿量与不变地塞米松尿量之比。最佳协变量模型为多西紫杉醇CL (l/h) = 356 × fu(alpha1) -AG × （1 - 0.17 × HPMT）（1 + 0.126 × DPC），其中fu（alpha1-AG）为多西紫杉醇未结合血浆分数，由α(1)-酸性糖蛋白血浆水平计算，HPMT为肝转移编码，存在时为1，不存在时为0。多西紫杉醇CL在不同基因型间无显著差异。结论。地塞米松可用作预测多西他赛清除率的探针，从而减少个体间的差异。
Purpose. A pilot study was conducted in 23 patients in order to assess the correlation between docetaxel clearance (CL) and pharmacokinetics of dexamethasone. Dexamethasone is mainly 6-beta hydroxylated by CYP3A4, and is regularly used as standard docetaxel premedication. Genotyping of known functional single nucleotide polymorphism (SNP) of CYP3A5 (G22893A) and mdr-1 (G2677T, G2677A, and C3435T) have been performed in order to tentatively correlate genotype with docetaxel and dexamethasone pharmacokinetics. Patients and methods. To be eligible for this study, patients were required to have a solid malignancy for which docetaxel was indicated. A population pharmacokinetic approach was used to determine individual pharmacokinetic parameters of both docetaxel and dexamethasone by Bayesian analysis, and to screen relationships between docetaxel CL and patients' demographic, phenotype and genotype covariates. Results. Three different pharmacokinetic parameters of dexamethasone were significantly correlated with docetaxel CL: dexamethasone plasma clearance (DPC) that ranged between 7.7 and 27.2 l/h, urinary amount of 6beta-hydroxydexamethasone, and the ratio between urinary amount of 6beta-hydroxydexamethasone and unchanged dexamethasone. The best covariate model was docetaxel CL (l/h) = 356 x fu(alpha1) - AG x (1 - 0.17 x HPMT)(1 + 0.126 x DPC) where fu(alpha1-AG) is the unbound plasma fraction of docetaxel calculated from alpha(1)-acid glycoprotein plasma level, and HPMT is hepatic metastasis coded as 1 if present or 0 if absent. No significant difference in docetaxel CL was observed between the several genotypes. Conclusions. Dexamethasone may be used as a probe to predict docetaxel clearances, hence reducing interindividual variability.