Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China.
Acta Pharmacol Sin. 2011 Mar;32(3):399-407. doi: 10.1038/aps.2010.218.
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.
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.
The activity of CYP2C8 was inhibited with an IC(50) value of 6.17±2.0 μmol/L. Erlotinib stimulated the midazolam 1'-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substrate-dependent: the IC(50) values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 μmol/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 μmol/L and 0.035 min(-1) for midazolam; 9.0 μmol/L and 0.045 min(-1) for testosterone; and 10.1 μmol/L and 0.058 min(-1) for nifedipine.
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.
确定厄洛替尼对 CYP3A 的影响，研究厄洛替尼在人肝微粒体（HLM）中对七种主要 CYP 同工酶的抑制作用的幅度和动力学，以评估厄洛替尼在体内药物相互作用中的作用。
使用 HPLC 或 UFLC 分析评估 7 种主要 CYP 同工酶（CYP1A2、CYP2A6、CYP3A、CYP2C9、CYP2D6、CYP2C8 和 CYP2E1）在 HLM 中的活性。采用两步孵育法研究厄洛替尼对 CYP3A 的时间依赖性抑制作用。
CYP2C8 的活性被 6.17±2.0 μmol/L 的 IC（50）值抑制。厄洛替尼刺激咪达唑仑 1'-羟化反应，但抑制 6β-羟睾酮和氧化硝苯地平的形成。厄洛替尼对 CYP3A 的抑制具有底物依赖性：抑制睾酮 6β-羟化和硝苯地平代谢的 IC（50）值分别为 31.3±8.0 和 20.5±5.3 μmol/L。厄洛替尼对 CYP3A 也表现出时间依赖性抑制，无论使用哪种探针底物：咪达唑仑的 K（I）和 k（inact）值分别为 6.3 μmol/L 和 0.035 min（-1）；睾酮为 9.0 μmol/L 和 0.045 min（-1）；硝苯地平为 10.1 μmol/L 和 0.058 min（-1）。
厄洛替尼对 CYP3A 的抑制具有底物依赖性，而其对 CYP3A 的时间依赖性抑制是底物非依赖性的。CYP3A 的时间依赖性抑制可能是药物相互作用的一个潜在原因，这表明在联合治疗的背景下，应注意评估厄洛替尼的安全性。
