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目的探讨伊曲康唑对合用药物药代动力学的影响机制,为临床上安全合理地利用合成药物提供依据。方法利用健康成人的肝细胞微粒体,将其分为加入不同浓度伊曲康唑的10个小组,浓度梯度为0.0、0.4、0.8、1.6、3.2μg/ml,每组做5个平行组,之后在其中五组加入肝细胞微粒体细胞色素的P450的同功酶1A2的底物非那西丁,在另外五组中加入同工酶3A4的底物睾酮,测量不同伊曲康唑下的同功酶1A2和3A4的相对活性。结果各浓度伊曲康唑组对同功酶1A2作用效果无明显差异,各浓度伊曲康唑组对同功酶3A4的作用较明显,同功酶3A4的活性随着伊曲康唑的浓度增大而减小,其减小到本实验的最大活性一半时的伊曲康唑的浓度为0.7μg/ml。结论伊曲康唑对健康成年人肝细胞微粒体细胞色素酶同功酶1A2的活性无显著影响;但是它对同功酶3A4的活性有明显抑制作用,极大地影响了同功酶3A4对合用药物药代动力学的各种参数。
Objective To investigate the mechanism of the effect of itraconazole on the pharmacokinetics of the combined drugs and provide the basis for the safe and rational use of synthetic drugs in clinical practice. Methods Hepatocyte microsomes from healthy adults were divided into 10 groups with different concentrations of itraconazole. The concentration gradients were 0.0, 0.4, 0.8, 1.6 and 3.2 μg / ml, with 5 parallel groups in each group. After that, among five groups, phenacetin which is the substrate of isozyme 1A2 of P450 of hepatocyte microsomal cytochrome was added, the substrate testosterone of isozyme 3A4 was added to the other five groups, Relative activity of isozymes 1A2 and 3A4. Results There was no significant difference in the effect of itraconazole 1A1 between the concentrations of itraconazole and the concentrations of itraconazole 3A4. The activity of isoenzyme 3A4 increased with the concentration of itraconazole Increases and decreases, the concentration of itraconazole reduced to half of the maximum activity of this experiment was 0.7 μg / ml. CONCLUSION Itraconazole has no significant effect on the activity of microsomal cytochrome C isoenzyme 1A2 in healthy adults; however, itraconazole has a significant inhibitory effect on the activity of isoenzyme 3A4, which greatly affects the activity of 3A4 Various parameters of pharmacokinetics of combined drugs.