| 19464879 |
Yong WP, Kim TW, Undevia SD, Innocenti F, Ratain MJ: R (+) XK469 inhibits hydroxylation of S-warfarin by CYP2C9. . Eur J Cancer. 2009 Jul;45(11):1904-8. Epub 2009 May 21.
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 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. CONCLUSION: 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. |
326(4,4,4,6) |