摘要
目的:观察伊曲康唑对健康成年人肝细胞微粒体细胞色素P450同功酶1 A2、3A4活性的作用,探讨伊曲康唑对合用药物药代动力学影响的机制,为临床上安全有效的联合用药提供实验依据。方法:采用健康成人肝细胞微粒体,分为对照组和不同浓度的伊曲康唑组,共12组,每组10个样本,伊曲康唑组分别加入血药浓度范围内不同对应浓度的伊曲康唑,对照组仅加入培养液,孵育30min 后,再加入CYP450同工酶1A2和3A4的相应底物(分别为非那西丁和睾酮)再孵育40 min。反应终止后用高效液相色谱仪测量代谢产物(分别为对乙酰氨基酚与6β-羟基睾酮)的峰面积代表1A2和3A4的相对活性。结果:各处理组细胞色素P450同功酶1A2的相对活性百分比与对照组比较无显著差异(P>0．05),而同功酶3A4的相对活性百分比随伊曲康唑浓度增加逐渐减小,各处理组与对照组比较均有显著差异(P<0．05或P<0．01)。细胞色素P450同功酶3A4的相对活性百分比减小到对照组50％时(IC50)伊曲康唑的浓度为0．14 μg／ml。结论:伊曲康唑在临床应用血药浓度范围内,对健康成年人肝细胞微粒体细胞色素P450酶同功酶1A2的活性无显著影响,然而对细胞色素P450同功酶3A4的活性有抑制作用,直接影响经3A4代谢的合用药物的血药浓度、半衰期等药代动力学参数。
Objective： To observe the effect of itraconazole on the activity of cytochromeP450 isoenzyme 1A2（CYP1A2） and 3A4 （CYP3A4） of health adult human primary hepatocyte microme, exploring the influencing mechanism of itraconazole to pharmacokinetics of combinactive applying medicine. Methods：The health adult human primary hepatocyte microsome was randomly divided into 12 groups for control and itraconazole with different concentrations in the range of clinical drug blood concentration, each group have 10 samples. Control groups were added culture fluid, itraconazole groups were added itmconazole with different concentration respectively, after cultured 30 minutes, substrates （phenacetin for CYP1A2, testosterone for CYP3A4） were added and cultured for another 40 minutes. Then metabolites （acetaminophen and 6-testosterone） peak area of them were measured with high performance liquid chromatogram, to assess the relative activities of CYP1A2 and 3A4. Results： There were no significant difference between itraconazole groups and control groups in either peak area of acetaminophen or relative activity of CYP1A2 （P〉0. 05）. But both the peak area of 6-testosterone and the relative activity of CYP3A4 were diminished gradually following the incremend of itraconazole＇s concentration. There were significant difference between every itraconazole groups and control groups in the peak area of 6-testosterone and the relative activity of CYP3A4 （P〈 0.05, P〈0.01）. The IC50 of itraconazole for CYP450 3A4 was 0.14 μg/mL. Conclusion：In the range of maximum clinical blood concentration, itraconazole can not inhibit the activity of CYP1A2 of health adult human primary hepatocyte microsome, but can inhibit the activity of CYP3A4, so that itraconazole can influence the blood concentration and half life of combinactive applying medicines that metabolized by CYP3A4.
出处
《中国临床医学》
北大核心
2005年第6期1144-1146,共3页
Chinese Journal of Clinical Medicine
