Posted on Authorea 1 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160157601.16885644 — This a preprint and has not been peer reviewed. Data may be preliminary. utpeCPioom eeivle ntehdoyaino iaoaa,wt eraigctltcrates catalytic decreasing with rivaroxaban, of hydroxylation the CYP2J2 in follows: involved as were isoforms CYP simulations Multiple docking Additionally, studies. recom- inhibitory Results with interactions. CYP-specific rivaroxaban molecular of via illustrate studies as to kinetic well used metabolic the were as Furthermore, via isoenzymes, compared recombinant isoforms. was and CYP CYP various isoforms (HLMs) binant of CYP microsomes participation liver of the human efficiency estimate of catalytic to presence evaluated the systematically in was rivaroxaban CYPs of stability metabolic The Methods insight new provide may which rivaroxaban, rivaroxaban. HLMs. of the involving mixed hydroxylation interactions Among in the drug 4F3, dominated ketoconazole clinical 2C19. CYP2J2 inhibitor by and into inhibitor Conclusion CYP2J2 > CYP3A-specific 2D6 CYP2J2-specific interactions. to the 2C9 CYP3A4, alkyl bound the by > and principally by 43.3% of intrinsic rivaroxaban bonds 2E1 of presence catalyzed that the > rate the showed that Notably, inhibition 2A6 simulations in 100-fold the molecular > 41.1% metabolism. Furthermore, and to by 3A7 rivaroxaban comparable 64- inhibited for > was 39-, was which 3A5 responsible hydroxylation nearly danazol, > isoforms rivaroxaban was 1A1 addition, major decreasing CYP2J2 > In four by with 4F3 the respectively. rivaroxaban, catalyzed were > rivaroxaban of 4F3 2D6 of hydroxylation and > clearance the 2D6 3A4 illustrate in 3A4, > to involved 2J2, CYP2J2 used were were CYPs, follows: simulations isoforms as docking CYP Additionally, recombi- isoforms. rates with Multiple studies. CYP rivaroxaban catalytic inhibitory Results of various CYP-specific studies of via kinetic interactions. micro- participation as metabolic molecular liver well via the human as compared estimate of was isoenzymes, to isoforms presence CYP CYP evaluated nant the of in systematically provide efficiency rivaroxaban was to catalytic of rivaroxaban the CYPs stability of Furthermore, recombinant metabolism metabolic the and The in (HLMs) Methods CYPs present multiple safety. somes The of (CYP). medication contributions P450 for the cytochrome information compare human and new by analyze mediated quantitatively metabolism to the is undergoes study anticoagulant, oral an Rivaroxaban, Aim Abstract 2020 1, October 4 3 2 1 Wang Changyuan Zhao Tingting Oral New a Rivaroxaban, of Anticoagulant Metabolism the to Cytochrome 2J2 Human P450 of Contribution Dominant the Identifying oal,teitisccerneo iaoaa aaye yCPJ a ery3- 4 n 0-odthat metabolism. 100-fold rivaroxaban and for 64- responsible 39-, nearly isoforms was major CYP2J2 four by the catalyzed rivaroxaban were of 4F3 clearance and intrinsic 2D6 the 3A4, Notably, 2J2, CYPs, the ffiito o available not Physics Affiliation Chemical University of Medical Institute Dalian Dalian of Hospital Affiliated First University Medical Dalian 1 awiChen Yanwei , 1 > in Meng Qiang , 3A4 > 2D6 2 aogWang Dalong , > 1 ujnSun Huijun , 4F3 > 1A1 > 1 1 1 3A5 ia Wang Liyan , ei Liu Kexin , > 3A7 > 4 n igigWu Jingjing and , 2A6 2 epiDong Peipei , > 2E1 π- ly od,carbon-hydrogen bonds, alkyl > 2C9 1 hnZhao Shan , > 1 C9 Among 2C19. 3 , Posted on Authorea 1 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160157601.16885644 — This a preprint and has not been peer reviewed. Data may be preliminary. ovnswr rmTda n.(ho S) oldhmnlvrmcooe eeprhsdfo Biore- from obtai- purchased were were CYP3A5 microsomes and liver CYP3A4 human human Pooled recombinant USA). cDNA-expressed sulfate 4 USA). (Ohio, dihydrogen at (Maryland, Inc. potassium clamationIVT Tedia, stored and Sigma- from and bisulfate from were purchased di