Results
Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban,
with decreasing catalytic rates as follows: CYP2J2 > 3A4
> 2D6 > 4F3 > 1A1 >
3A5 > 3A7 > 2A6 > 2E1
> 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6
and 4F3 were the four major isoforms responsible for rivaroxaban
metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by
CYP2J2 was nearly 39-, 64- and 100-fold that catalyzed by CYP3A4, 2D6
and 4F3, respectively. In addition, rivaroxaban hydroxylation was
inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor
danazol, which was comparable to the inhibition rate of 43.3% by the
CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore,
molecular simulations showed that rivaroxaban principally bound to
CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds and alkyl interactions.