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	Time Dependent Inhibition Of CYP3A4 Was The Potent Reason For High-Frequency Clinical Drug-Drug Interaction Of Erlotinib
	Dong PP(董佩佩) ; Fang ZZ(房中则) ; Zhang YY(张延延) ; Ge GB(葛广波) ; Mao YX(毛玉玺) ; Zhu LL(朱亮亮) ; Li W(李巍) ; Yang L(杨凌)
	2010-05-16
会议名称	18th international symposium on microsomes and drug oxidations
会议日期	2010-5-16
会议地点	中国
页码	259/1
通讯作者	ling yang
中文摘要	background: to expain the high frenquency drug-drug interactions of erlotinib, the inhibition potential and kinetic information of erlotinib to seven cyp isoforms was investigated. meanwhile the in vivo drug-drug interaction magnitude was extrapolated from in vitro data. the activities of seven cyp isoforms (cyp3a4, cyp1a2, cyp2a6, cyp2e1, cyp2d6, cyp2c9, cyp2c8) in human liver microsomes were investigated following co- or pre-incubation with erlotinib. a two-step incubation method was used to examine in vitro tdi of erlotinib. reversible and tdi prediction equations were employed to extrapolate in vivo drug-drug interaction magnitude from in vitro data. results: among seven cyp isoforms tested, the activities of cyp3a4 and cyp2c8 were inhibited with an ic50 of 31.8±7.7 μm and 6.17±1.8 μm. kinetic analysis showed that inhibition of cyp3a4 and cyp2c8 by erlotinib was best fit to a competitive manner with ki value of 20.8 μm and 6.2μm. erlotinib also exhibited tdi to cyp3a4. the inactivation parameters (ki and kinact) were calculated to be 19.0 μm and 0.18 min-1. for three different doses of erlotinib (50,100,150 mg/day), the auc of coadministered drugs was predicted to increase 0.8%, 0.9% and 1.5% using unbound portal vein concentration with reversible inhibition prediction equation for cyp3a4. as for cyp2c8, the increasement of auc was predicted to be 2.7%, 3.2% and 5.3%. with tdi prediction equation for three different doses for cyp3a4, the auc was estimated to increase by 8.98~467.5%, 9.9~868.1% and 10.2~1268.0 using unbound systemic concentration for fm from 0.1 to 1 separately. conclusions: tdi of erlotinib potentially explains the high-frequency clinical drug-drug interaction of erlotinib. attentions should be payed when the drugs which are mainly cleared by cyp3a4 were coadminstered with erlotinib.
会议主办者	institute of materia medica chinese academy of medical sciences & peking union medical college
学科主题	物理化学
语种	中文
内容类型	会议论文
源URL	[http://159.226.238.44/handle/321008/114062]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
推荐引用方式 GB/T 7714	Dong PP,Fang ZZ,Zhang YY,et al. Time Dependent Inhibition Of CYP3A4 Was The Potent Reason For High-Frequency Clinical Drug-Drug Interaction Of Erlotinib[C]. 见:18th international symposium on microsomes and drug oxidations. 中国. 2010-5-16.

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