Subject Area物理化学
Identification of CYP isoforms involved in metabolism of corynoline and assessment of CYP-mediated drug-drug interaction
Fang ZZ(房中则); Yang L(杨凌); Ling Yang
Conference Name18th International Symposium on Microsomes and Drug Oxidations
Conference Date2010-5-16
Conference Place中国
Funding OrganizationInstitute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College
AbstractCorynoline, an isoquinoline alkaloid isolated from the genus Corydalis, has been demonstrated to show multiple pharmacological effects including inhibition of acetylcholinesterase, inhibition of cell adhesion, fungitoxic and cytotoxic activity (Kim, 2002; Kamigauchi et al., 2005). Although much attention has been focused on its pharmacological study, information on the metabolism of corynoline and CYP inhibitory potential still remains unclear. The present study focused on its metabolism and metabolism-based drug-herb interactions. After corynoline was incubated with human liver microsomes (HLMs) in the presence of NADPH, two demethylenated metabolites (M-1 and M-2) were formed. Chemical inhibition experiment and assays with recombinant CYP isoforms showed CYP2C9 was mainly involved in the formation of M-1 and CYP3A4 mainly catalyzed the production of M-2. Among seven major CYP isoforms tested, corynoline showed strong inhibitory effects on the activities of CYP3A4 and CYP2C9, with an IC50 of 3.3±0.9 μM and 31.5±0.5 μM, respectively. Kinetic analysis showed that inhibition of CYP3A4 by corynoline was best fit to a noncompetitive manner with Ki of 3.2 μM, while inhibition of CYP2C9 by corynoline was best fit to a competitive manner with Ki of 6.3 μM. Additionally, corynoline exhibited time-dependent inhibition (TDI) to CYP3A4. The inactivation kinetic parameters (KI and kinact) were calculated to be 6.8 μM and 0.07 min-1, respectively. These data are helpful for the clinical application of corynoline and corynoline-containing herbs.
Document Type会议论文
Corresponding AuthorLing Yang
Recommended Citation
GB/T 7714
Fang ZZ,Yang L,Ling Yang. Identification of CYP isoforms involved in metabolism of corynoline and assessment of CYP-mediated drug-drug interaction[C],2010:258/1.
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