R(+)XK469 inhibits hydroxylation of S-warfarin by CYP2C9.
BACKGROUND
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 K(i) values of R(+)XK469 were estimated to be 959+/-426 microM for human liver microsomes and to be 377+/-92 microM for CYP2C9.


CONCLUSIONS
At the recommended phase II dose of R(+)XK469, the ratio of C(max)/K(i) 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.
Yong
Wei Peng
WP
Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL 60637, USA.
Kim
Tae Won
TW
Undevia
Samir D
SD
Innocenti
Federico
F
Ratain
Mark J
MJ
D000925:Anticoagulants / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001667:Binding, Competitive; D002478:Cells, Cultured; D065729:Cytochrome P-450 CYP2C9; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D006900:Hydroxylation; D019934:International Normalized Ratio; D008862:Microsomes, Liver / Q000201:enzymology*; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use*; D012044:Regression Analysis; D059005:Topoisomerase II Inhibitors; D014859:Warfarin / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use
D000925:Anticoagulants; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011810:Quinoxalines; D059005:Topoisomerase II Inhibitors; C118180:XK 469; D014859:Warfarin; C087837:7-hydroxywarfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D004250:DNA Topoisomerases, Type II