Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Br J Clin Pharmacol. 2010 Feb;69(2):193-9. doi: 10.1111/j.1365-2125.2009.03572.x.
To investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolate in vivo noscapine-warfarin interaction magnitude 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 preincubation with noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data.
Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC(50) of 10.8 +/- 2.5 microm and 13.3 +/- 1.2 microm. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with K(i) value of 8.8 microm, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with K(i) value of 5.2 microm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (K(I) and k(inact)) were calculated to be 9.3 microm and 0.06 min(-1) for CYP3A4 and 8.9 microm and 0.014 min(-1) for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using C(max) or 0.5% and 0.4% using unbound C(max) with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using C(max) or 41.8% and 32.7% using unbound C(max) with TDI prediction equation.
TDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction.
研究北美豚草碱对 7 种 CYP 同工酶的抑制潜力和动力学信息，并从体外数据推断体内北美豚草碱-华法林相互作用的程度。
在人肝微粒体中，通过共孵育或预孵育北美豚草碱，研究 7 种 CYP 同工酶（CYP3A4、CYP1A2、CYP2A6、CYP2E1、CYP2D6、CYP2C9、CYP2C8）的活性。采用两步孵育法检测北美豚草碱的体外时间依赖性抑制（TDI）。采用可逆和 TDI 预测方程，从体外数据推断体内北美豚草碱-华法林相互作用的程度。
在所测试的 7 种 CYP 同工酶中，CYP3A4 和 CYP2C9 的活性受到强烈抑制，IC（50）分别为 10.8±2.5μm 和 13.3±1.2μm。动力学分析表明，北美豚草碱对 CYP2C9 的抑制最好拟合为非竞争性类型，K（i）值为 8.8μm，而北美豚草碱对 CYP3A4 的抑制最好拟合为竞争性类型，K（i）值为 5.2μm。北美豚草碱对 CYP3A4 和 CYP2C9 也表现出 TDI。计算 CYP3A4 和 CYP2C9 的失活参数（K（I）和 k（inact））分别为 9.3μm 和 0.06min（-1）和 8.9μm 和 0.014min（-1）。使用 C（max）的可逆抑制预测方程，（S）-华法林和（R）-华法林的 AUC 预计分别增加 1.5%和 1.1%，而使用未结合 C（max）的预测方程，（S）-华法林和（R）-华法林的 AUC 预计分别增加 0.5%和 0.4%。使用 C（max）的 TDI 预测方程，（S）-华法林和（R）-华法林的 AUC 预计分别增加 110.9%和 48.9%，而使用未结合 C（max）的预测方程，（S）-华法林和（R）-华法林的 AUC 预计分别增加 41.8%和 32.7%。
北美豚草碱对 CYP3A4 和 CYP2C9 的 TDI 可能解释了临床北美豚草碱-华法林相互作用。
