PT - JOURNAL ARTICLE AU - Yanjun Hong AU - Yvonne Mei Fen Chia AU - Ray Hng Yeo AU - Gopalakrishnan Venkatesan AU - Siew Kwan Koh AU - Christina Li Lin Chai AU - Lei Zhou AU - Pipin Kojodjojo AU - Eric Chun Yong Chan TI - Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone AID - 10.1124/mol.115.100891 DP - 2015 Jan 01 TA - Molecular Pharmacology PG - mol.115.100891 4099 - http://molpharm.aspetjournals.org/content/early/2015/10/21/mol.115.100891.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/10/21/mol.115.100891.full AB - Dronedarone is an antiarrhythmic agent approved in 2009 for the treatment of atrial fibrillation. In-house preliminary study demonstrated that dronedarone inhibits CYP3A4 and CYP3A5 in a time-dependent manner. This study aimed to investigate the inactivation of CYP450 by dronedarone. We demonstrated for the first time that both dronedarone and its main metabolite, N-desbutyl dronedarone (NDBD), inactivate CYP3A4 and CYP3A5 in a time-, concentration-, and NADPH-dependence manner. For inactivation of CYP3A4, KI and kInact are 0.87 μM and 0.039 min-1 respectively for dronedarone, and 6.24 μM and 0.099 min-1 respectively for NDBD. For CYP3A5 inactivation, KI and kInact are 2.19 μM and 0.0056 min-1 for dronedarone, and 5.45 μM and 0.056 min-1 for NDBD. The partition ratios for the inactivation of CYP3A4 and CYP3A5 by dronedarone are 51.1 and 32.2, and by NDBD are 35.3 and 36.6. Testosterone protected both CYP3A4 and CYP3A5 from inactivation by dronedarone and NDBD. While the presence of Soret peak confirmed the formation of quasi-irreversible metabolite-intermediate (MI) complex between dronedarone/NDBD and CYP3A4/5, partial recovery of enzyme activity by potassium ferricyanide illuminated an alternative irreversible mechanism-based inactivation (MBI). MBI of CYP3A4 and CYP3A5 was further supported by the discovery of GSH adducts derived from the quinone oxime intermediates of dronedarone and NDBD. In conclusion, dronedarone and NDBD inactivate CYP3A4 and CYP3A5 via unique dual mechanisms of MBI and formation of MI complex. Our novel findings contribute new knowledge for future investigation of the underlying mechanisms associated with dronedarone-induced hepatotoxicity and clinical drug-drug interactions (DDIs).