Identifying the Dominant Contribution of Human Cytochrome P450 2J2 to
the Metabolism of Rivaroxaban, a New Oral Anticoagulant
Abstract
Aim Rivaroxaban, an oral anticoagulant, undergoes the metabolism
mediated by human cytochrome P450 (CYP). The present study is to
quantitatively analyze and compare the contributions of multiple CYPs in
the metabolism of rivaroxaban to provide new information for medication
safety. Methods The metabolic stability of rivaroxaban in the presence
of human liver microsomes (HLMs) and recombinant CYPs was systematically
evaluated to estimate the participation of various CYP isoforms.
Furthermore, the catalytic efficiency of CYP isoforms was compared via
metabolic kinetic studies of rivaroxaban with recombinant CYP
isoenzymes, as well as via CYP-specific inhibitory studies.
Additionally, docking simulations were used to illustrate molecular
interactions. 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. Conclusion CYP2J2
dominated the hydroxylation of rivaroxaban, which may provide new
insight into clinical drug interactions involving rivaroxaban.