title: Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid.
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 (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.
authors.affiliation: Division of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland, New Zealand. phazsf@nus.edu.sg
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
authors.forename: Philip
authors.initials: P
authors.lastname: Kestell
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015507:Drugs, Investigational / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D008657:Metabolic Clearance Rate / Q000502:physiology*; D008862:Microsomes, Liver / Q000378:metabolism*; D014966:Xanthenes / Q000378:metabolism / Q000493:pharmacokinetics*; D044004:Xanthones
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D015507:Drugs, Investigational; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D003577:Cytochrome P-450 Enzyme System