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目的探讨新型酪氨酸激酶抑制剂对hERG钾通道电流的影响。方法应用全细胞膜片钳技术,记录HEK293细胞异源表达的hERG钾电流,观察新型酪氨酸激酶抑制剂对hERG钾通道电流的抑制作用。结果新型酪氨酸激酶抑制剂能作用于hERG钾通道,并以浓度依赖的方式抑制hERG钾电流,半数抑制浓度(IC50)分别为PA1101(10.80±3.01)μmol/L,PA1102(9.55±1.81)μmol/L,PA1103(1.69±0.26)μmol/L,PA1104(1.17±0.49)μmol/L,PA1105(0.08±0.02)μmol/L,PA1106(0.001 9±0.000 7)μmol/L。结论新型酪氨酸激酶抑制剂对hERG钾通道有较强烈的阻断作用,建议结合临床使用剂量与血药浓度进行安全性评估。
Objective To investigate the effect of novel tyrosine kinase inhibitors on potassium channel current in hERG. Methods Whole cell patch clamp technique was used to record the hERG potassium currents heterologously expressed in HEK293 cells. The inhibitory effect of novel tyrosine kinase inhibitors on potassium channel current was observed. Results The novel tyrosine kinase inhibitor could act on the hERG potassium channel and inhibit the hERG potassium currents in a concentration-dependent manner. The half-maximal inhibitory concentrations (IC50) were PA1101 (10.80 ± 3.01) μmol / L and PA1102 (9.55 ± 1.81) PA1105 (1.69 ± 0.26) μmol / L, PA1104 (1.17 ± 0.49) μmol / L, PA1105 (0.08 ± 0.02) μmol / L and PA1106 (0.001 9 ± 0.000 7) μmol / L. Conclusion The new tyrosine kinase inhibitor has a strong blocking effect on hERG potassium channels. It is suggested that the combination of clinical dose and plasma concentration for safety assessment.