Subject Area物理化学
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); 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
AbstractBackground: 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.
Document Type会议论文
Corresponding AuthorLing Yang
Recommended Citation
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],2010:259/1.
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