Please use this identifier to cite or link to this item: https://doi.org/10.1200/JCO.2002.01.025
Title: Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies
Authors: Goh, B.-C.
Lee, S.-C. 
Wang, L.-Z. 
Fan, L.
Guo, J.-Y. 
Lamba, J.
Schuetz, E.
Lim, R.
Lim, H.-L.
Ong, A.-B.
Lee, H.-S.
Issue Date: 1-Sep-2002
Source: Goh, B.-C., Lee, S.-C., Wang, L.-Z., Fan, L., Guo, J.-Y., Lamba, J., Schuetz, E., Lim, R., Lim, H.-L., Ong, A.-B., Lee, H.-S. (2002-09-01). Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. Journal of Clinical Oncology 20 (17) : 3683-3690. ScholarBank@NUS Repository. https://doi.org/10.1200/JCO.2002.01.025
Abstract: Purpose: To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype. Patients and Methods: 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 C3435Tpolymorphism of MDR1. Results: 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. Conclusion: 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. © 2002 by American Society of Clinical Oncology.
Source Title: Journal of Clinical Oncology
URI: http://scholarbank.nus.edu.sg/handle/10635/105941
ISSN: 0732183X
DOI: 10.1200/JCO.2002.01.025
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

215
checked on Feb 22, 2018

WEB OF SCIENCETM
Citations

203
checked on Jan 22, 2018

Page view(s)

32
checked on Feb 19, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.