摘要
目的研究厚朴抗炎有效成分(E)-5-allyl-3'-(prop-1-enyl)biphenyl-2,4'-diol(HK-1)在人、大鼠、比格犬、猴和小鼠的肝微粒体中的代谢稳定性,确定HK-1在大鼠肝微粒体中代谢表型。方法将HK-1在5个种属肝微粒体中孵育,采用UPLC-MS/MS检测方法,通过测定HK-1的剩余浓度,考察它们的代谢稳定性并外推其体内代谢清除率。化学抑制剂法鉴定在大鼠肝微粒体中HK-1的代谢表型。结果 HK-1在人、大鼠、比格犬、猴和小鼠5个种属肝微粒体中半衰期(t_(1/2))分别为9.04、7.36、2.17、4.94、18.09 min;肝微粒体中固有清除率CL_(int)分别为153.40、188.20、639.02、280.60、76.60 m L/(min·mg蛋白);体内固有清除率CL'_(int)分别为151.87、338.76、949.21、416.69、301.61 m L/(min·kg)。在大鼠肝微粒体中HK-1主要被细胞色素CYP2E1、CYP2C、CYP1A2催化代谢。结论HK-1在肝微粒体中由多种酶代谢且代谢很快,其中人肝微粒体和大鼠肝微粒体中半衰期和固有清除率相似,可将大鼠肝微粒体预估人肝微粒体不良反应的风险。
AIM To investigate the metabolic stability of（ E）-5-allyl-3＇-（ prop-1-enyl） biphenyl-2,4＇-diol（ HK-1） isolated from Magnolia officinalis Rehd. et Wils. in human,rat,Beagle dog,monkey and mouse liver microsomes and to determine cytochrome P450（ CYP450） inhibitory potential of HK-1. METHODS The concentrations of HK-1 were measured by a UPLC-MS/MS method to evaluate the metabolic stability of HK-1. The CYP450 phenotyping of HK-1 was identified by specific inhibitors of isoforms in rat microsomal incubation system.RESULTS HK-1 could be metabolized in human,rat,Beagle dog,monkey and mouse liver microsomes. The corresponding half-life t（1/2）were 9. 04,7. 36,2. 17,4. 94,and 18. 09 min; intrinsic clearance（ CL（int）） were153. 40,188. 20,639. 02,280. 60,and 76. 60 m L/（ min · mg protein）; intrinsic clearance（ CL＇（int）） were151. 87,338. 76,949. 21,416. 69,and 301. 61 m L/（ min·kg）,respectively. CYP2E1,CYP2 C and CYP1A2 were found to be the major CYP isoforms involved in HK-1 metabolism. CONCLUSION HK-1 could be metabolically eliminated in a short amount of time and by multiple enzymes. Its metabolism is similar between human and rat liver microsomes. Therefore further study with rat liver microsomes can be used as a good indicator of the risks involved with human liver microsomes.
出处
《中成药》
CAS
CSCD
北大核心
2016年第4期723-728,共6页
Chinese Traditional Patent Medicine
基金
十二五重大新药创制(2012ZX09103101-066)
