Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid

Zhou, S, Kestell, P, Baguley, B and Paxton, J 2003, 'Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid', Biochemical Pharmacology, vol. 65, no. 11, pp. 1853-1865.


Document type: Journal Article
Collection: Journal Articles

Title Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid
Author(s) Zhou, S
Kestell, P
Baguley, B
Paxton, J
Year 2003
Journal name Biochemical Pharmacology
Volume number 65
Issue number 11
Start page 1853
End page 1865
Total pages 13
Publisher Elsevier Inc.
Abstract Cancer chemotherapy is characterized by significant interindividual variations in systemic clearance, therapeutic response, and toxicity. These variations are due mainly to genetic factors, leading to alterations in drug metabolism and/or target proteins. The aim of this study was to determine, using a human liver bank (N=14), the interindividual variations in the expression and activity of liver enzymes that metabolize the investigational anticancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), i.e cytochrome P450 (CYP1A2) and uridine diphosphate glucuronosyltransferase (UGT1A9/2B7). In addition, interindividual variations in enzyme inhibition, hydrolysis of DMXAA acyl glucuronide (DMXAA-G) by plasma and hepatic microsomes, and the binding of DMXAA by plasma proteins also were examined. The results indicated that there was approximately one order of magnitude of interindividual variation in the expression of CYP1A2 and UGT2B7, activity of the enzymes toward DMXAA, and inhibition potency (Image 50) by diclofenac, cyproheptadine, and α-naphthoflavone. The enzyme activities toward DMXAA and Image 50 values were closely correlated with enzyme expression. There was a smaller (2- to 3-fold) variation in the enzyme-catalyzed hydrolysis of DMXAA acyl glucuronide in human plasma and liver microsomes (N=6) and in the binding of DMXAA by plasma proteins in humans. In conclusion, the interindividual variability of DMXAA disposition observed in vitro might reflect the greater elimination variability (>one order of magnitude) in Phase I cancer patients. The variability in DMXAA clearance in these cancer patients would be due mainly to differences in its metabolism and its metabolic inhibition by co-administered drugs. To a lesser extent, variability in the clearance of DMXAA could be due to the hydrolysis of its acyl glucuronide and/or its binding to plasma proteins. Further study is needed to examine the genotype–phenotype relationship, and the result, together with therapeutic drug monitoring may provide a useful strategy for optimizing DMXAA treatment.
Subject Pharmacogenomics
Keyword(s) CYP
DMXAA
inhibition
interindividual variation
UGT
DOI - identifier 10.1016/S0006-2952(03)00189-8
Copyright notice © 2003 Elsevier Science Inc. All rights reserved.
ISSN 0006-2952
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