title: High-throughput screening of potential inhibitors for the metabolism of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid.
abstract: By screening potential inhibitors of drug metabolism using the in vitro models, potential drug-drug interactions in vivo may be predicted with the use of appropriate pharmacokinetic principles. This study aimed to develop a rapid screening system using human liver microsomes to efficiently identify the potential inhibitors of DMXAA metabolism. Initial IC50 was estimated by using a two-point method, and then Ki values were determined if required and compared with those initial IC50 values. More than 100 compounds including known substrates and inhibitors of human uridine diphosphate glucuronosyltransferases (UGTs) and cytochrome P450 (CYP), anti-cancer drugs and xanthenone analogues were screened for their inhibitory effect on DMXAA glucuronidation and 6-methylhydroxylation in human liver microsomes. Both metabolites of DMXAA, DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA), formed in human liver microsomes were quantitated by validated HPLC methods. The results indicated that there was a significant relationship (r2 = 0.966, P < 0.001) between the two-point IC50 values and the apparent Ki values for 20 compounds showing significant inhibitory effects on DMXAA metabolism, suggesting the usefulness of the two-point determination for the initial screening of compounds. This study has been completed using a strategy for rapid HPLC analysis and thus provided early access to detailed information for potential inhibitors of DMXAA metabolism and allows for further DMXAA-drug interaction studies.
authors.affiliation: Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand. shufeng.zhou@auckland.ac.nz
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zho
authors.forename: Daniel
authors.initials: D
authors.lastname: Chiang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chin
authors.forename: Philip
authors.initials: P
authors.lastname: Kestell
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
mesh_terms: D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013050:Spectrometry, Fluorescence; D014966:Xanthenes / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D044004:Xanthones
chemical_list: D000970:Antineoplastic Agents; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan