R(+)XK469 inhibits hydroxylation of S-warfarin by CYP2C9

• Published in: European journal of cancer (1990) Vol. 45; no. 11; pp. 1904 - 1908
• Main Authors: Yong, Wei Peng, Kim, Tae Won, Undevia, Samir D, Innocenti, Federico, Ratain, Mark J
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01-07-2009; Elsevier
• Subjects: Anticoagulants - therapeutic use; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - metabolism; Binding, Competitive; Biological and medical sciences; Cells, Cultured; CYP2C9; Cytochrome P-450 CYP2C9; DNA Topoisomerases, Type II; DNA-Binding Proteins - antagonists & inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug interaction; Drug Interactions; Enzyme Inhibitors - therapeutic use; Hematology, Oncology and Palliative Medicine; Humans; Hydroxylation; International Normalized Ratio; Medical sciences; Microsomes, Liver - enzymology; Pharmacokinetics; Pharmacology. Drug treatments; Quinoxalines - pharmacology; Quinoxalines - therapeutic use; Regression Analysis; Topoisomerase II Inhibitors; Tumors; Warfarin; Warfarin - analogs & derivatives; Warfarin - analysis; Warfarin - therapeutic use; XK469; CYP2C9; Warfarin; Drug interaction; Pharmacokinetics; XK469; Hydroxylation; Enzyme; Coumarine derivatives; Cytochrome P450; Antivitamin K; Cancerology; Inhibitor; CYP2C9 gene
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2009.04.032

Abstract Introduction XK469 is a novel topoisomerase II inhibitor structurally akin to several propionic acid derivatives, such as ibuprofen and diclofenac, which are metabolised by CYP2C9. We report eight subjects who experienced significant elevation of INR while receiving concomitant R(+)XK469 and warfarin. The aim of the study is to investigate whether R(+)XK469 interacts with S-warfarin by inhibition of CYP2C9. Methods The effect of R(+)XK469 on S-warfarin hydroxylation was determined by the measurement of S-7-hydroxywarfarin formation in pooled human liver microsomes and cDNA-expressed CYP2C9. Results R(+)XK469 competitively inhibited S-warfarin hydroxylation. The Ki values of R(+)XK469 were estimated to be 959 ± 426 μM for human liver microsomes and to be 377 ± 92 μM for CYP2C9. Conclusion At the recommended phase II dose of R(+)XK469, the ratio of Cmax / Ki is >1. This suggests that coadministration of R(+)XK469 and warfarin results in a clinically significant pharmacokinetic interaction due to CYP2C9 inhibition by R(+)XK469.