Pharmacogenetic Pathway Analysis of Docetaxel Elimination

被引：133

作者：

Baker, S. D. ^{[1
]}

Verweij, J. ^{[2
]}

Cusatis, G. A. ^{[3
]}

van Schaik, R. H. ^{[4
]}

Marsh, S. ^{[5
]}

Orwick, S. J. ^{[1
]}

Franke, R. M. ^{[1
]}

Hu, S. ^{[1
]}

Schuetz, E. G. ^{[1
]}

Lamba, V. ^{[1
]}

Messersmith, W. A. ^{[3
]}

Wolff, A. C. ^{[3
]}

Carducci, M. A. ^{[3
]}

Sparreboom, A. ^{[1
]}

机构：

[1] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[2] Dr Daniel Den Hoed Canc Ctr, Erasmus MC, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands

[3] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Oncol, Baltimore, MD USA

[4] Erasmus MC, Dept Clin Chem, Rotterdam, Netherlands

[5] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2009年 / 85卷 / 02期

基金：

美国国家卫生研究院;

关键词：

CANCER-PATIENTS; POPULATION PHARMACOKINETICS; PACLITAXEL PHARMACOKINETICS; FUNCTIONAL-SIGNIFICANCE; SUBSTRATE-SPECIFICITY; CLINICAL PRESENTATION; DUTCH CAUCASIANS; PROSTATE TUMORS; GENETIC VARIANT; OVARIAN-CANCER;

D O I：

10.1038/clpt.2008.95

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. among the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. none of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). however, the simultaneous presence of the CYP3A4*1B and CYP3A5*1A alleles was associated with a 64% increase in docetaxel clearance (P = 0.0015), independent of both sex and CYP3A activity (as determined using the erythromycin breath test). This haplotype was also associated with increased midazolam clearance in another population (P = 0.0198). an analysis of the CYP3A locus among CEPH-HapMap samples revealed that CYP3A4*1B is present exclusively among a subset of CYP3A5 expressors. Therefore, future studies should first stratify the population on the basis of CYP3A5 genotype and then compare CYP3A activity between individuals with and without the CYP3A4*1B allele.

引用

页码：155 / 163

页数：9

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