多西紫杉醇
药代动力学
咪唑安定
医学
药物遗传学
药理学
CYP3A5
CYP3A型
CYP3A4型
药效学
基因型
内科学
人口
Cmin公司
肿瘤科
化疗
生物
最大值
细胞色素P450
遗传学
新陈代谢
镇静
基因
环境卫生
作者
Boon-Cher Goh,Soo Chin Lee,Lingzhi Wang,Li Fan,Jiayi Guo,Jatinder K. Lamba,Erin G. Schuetz,Robert C. Lim,Hui Jun Lim,Ashley Li Kuan Ong,How-Sung Lee
标识
DOI:10.1200/jco.2002.01.025
摘要
To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype.We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates. Midazolam was administered intravenously to these patients at least 2 days before docetaxel treatment, and systemic clearances of both drugs were correlated. Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1.Thirty-two patients were enrolled, of whom 31 had full pharmacokinetic data sets. Docetaxel clearance correlated with midazolam clearance, body-surface area, serum albumin, and performance status. Docetaxel and midazolam clearances were normally distributed. In multiple linear regression analyses, midazolam clearance and performance status were the only significant covariates of docetaxel clearance, and the area under the curve of docetaxel, serum levels of alpha-1-acid glycoprotein, and ALT were significant predictors of nadir neutrophil count. No polymorphisms were detected in the 5' regulatory region of CYP3A4. Nine patients of 25 studied were homozygous for the CYP3A5*3 genotype, and had lower mean clearance of midazolam but not docetaxel. The T/T genotype at the C3435T of MDR1, which is associated with reduced P-glycoprotein function, was found in eight of 27 patients.Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.
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