Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib
Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib
复制标题
厄洛替尼对 CYP3A 催化活性的底物依赖性调节
DOI：
10.1038/aps.2010.218
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发表时间：
2011-03-01
影响因子：
8.2
通讯作者：
Yang, Ling
中科院分区：
文献类型：
--
作者：
Dong, Pei-pei;Fang, Zhong-ze;Yang, Ling
目的：探讨厄洛替尼对细胞色素P3A(CyP3A)的影响，研究厄洛替尼对人肝微粒体(HLMs)中7种主要CYP异构体的抑制幅度和动力学，以评价其在体内药物相互作用中的作用。方法：采用高效液相色谱(HPLC)或超高效液相色谱(UFLC)分析7种主要CYP亚型(CYP1A2、CYP2A6、CYP3A、CYP2C9、CYP2D6、CYP2C8和CYP2E1)的活性。结果：厄洛替尼对细胞色素P3A的活性有抑制作用，IC50值为6.17+/-2.0mU·mol/L，对咪达唑仑1‘-羟基反应有刺激作用，但对6-羟基睾酮和氧化硝苯地平的生成有抑制作用。厄洛替尼对细胞色素P3A的抑制作用具有底物依赖性，抑制睾酮6β羟化的IC50值为31.3+/-8.0，抑制硝苯地平代谢的IC50值为20.5+/-5.3mU·mol/L。无论使用何种底物，厄洛替尼对细胞色素P3A的抑制作用均呈时间依赖性：咪达唑仑的K-I和k分别为6.3mU/L和0.035分钟(-1)，睾酮分别为9.0mU/L和0.045分钟(-1)，硝苯地平分别为10.1mU/L和0.058分钟(-1)。CyP3A的时间依赖性抑制可能是药物-药物相互作用的一个可能原因，这表明应该重视对厄洛替尼的安全性评估，特别是在联合治疗的背景下。
Aim: To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo.Methods: The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A.Results: The activity of CYP2C8 was inhibited with an IC50 value of 6.17 +/- 2.0 mu mol/L. Erlotinib stimulated the midazolam 1'-hydroxy reaction, but inhibited the formation of 6 beta-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substrate-dependent: the IC50 values for inhibiting testosterone 6 beta-hydroxylation and nifedipine metabolism were 31.3 +/- 8.0 and 20.5 +/- 5.3 mu mol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K-I and k(inact) were 6.3 mu mol/L and 0.035 min(-1) for midazolam; 9.0 mu mol/L and 0.045 min(-1) for testosterone; and 10.1 mu mol/L and 0.058 min(-1) for nifedipine.Conclusion: The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrate-independent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.