hERG in vitro interchange factors-development and verification

作者：Wisniowska Barbara; Polak Sebastian^*

来源：Toxicology Mechanisms and Methods, 2009, 19(4): 278-284.

DOI：10.1080/15376510902777194

• Extrapolation factor
• hERG
• IC50
• cordiotoxicity
• drug development

Literature data analysis shows that the hERG interactions experiments carried out in different conditions with use of different in vitro systems for the same substance can result with different IC(50) values. One of the initial components of the proposed drug development supporting system is a set of extrapolation factors enabling the unrestricted choice of some elements of the experimental procedure without resultin significant depreciation. Therefore the main objective of this work was to develop the extrapolation factors allowing inter-system (HEK, CHO, XO) and inter-temperature (room and physiological) IC(50) values comparison based on the collected and analyzed hERG IC(50) data. The efficiency of the obtained factors was then verified in comparison with the native HEK IC(50) values at the physiological temperature. Low values of all the error estimates for the proposed factors evidence their good predictive value which, in turn, ground their application during drug candidates cardiotoxic risk evaluation or further in silico modeling. Utilization of the proposed factors during drug development process allows a more flexible choice of experimental model to exploit in the electrophysiological investigations, as well as makes it possible to experiment in ambient temperature, which is more convenient. The factors also facilitate data comparisons and allow one to draw reasonable conclusions for further extrapolation.

• 出版日期2009-5