主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
[Background] combretastatin A4-phosphate (CA4P) is the best-known tumor vascular disrupting agents (VDAs). It has been reported to possess QTc prolongation cardiotoxicity effects in clinical researchs but there was no report of torsades de pointes (Tdp). The cellular mechanism of QTc prolongation caused by CA4P was unclear. This is the first electrophysiological mechanism investigated about CA4P and even for VDAs prolonged of the QT interval.
[Method] Using the traditional whole-cell patch clamp techniques to verify the effects of CA4P in hERG k+ channel current expressed in human embryonic kidney (HEK293) cells and action potential duration (APD) in Ventricular myocytes of guinea-pigs. We aslo evaluated the safety margin ratio. Safety margin ratio indicated that CA4P has the high drug's hERG liability.
[Result] At the concentrations of 3, 10, 30, 100 and 300umol/L CA4P, the tail current inhibition rations were 9.8%, 19.2%, 44.3%, 77.2% and 100%, respectively. The half-maximal inhibitory concentration (IC50) was 54.9uM. Maximal safety margin ratio was 0.36 fold. Time-dependence of hERG current block by CA4P(300umol/L), the tail current was completely inhibited in 8min. For the current-voltage (I-V) relationships, the percentage inhibition in the hERG currents by 30umol/L CA4P at 10mV, 20mV, 30mV, 40mV and 50mV was 9.9%, 23.7%, 27.3%, 32.3% and 31.8%, respectively. CA4P (10, 100 umol/L) significantly prolonged the action potential duration at 50% of repolarization (APD50) by 15.77% and 42.01%, and the action potential duration at 90% of repolarization (APD90) by 10.15% and 31.36%.
