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 (IC(50)) by
diclofenac,
cyproheptadine, and
alpha-naphthoflavone. The
enzyme activities toward
DMXAA and IC(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.