Influence of electrolyte imbalance, acidosis and temperature on block of hERG.
For each drug, we measured how the potency of hERG block was modified by i) kalaemic variation (3/5/7 mM K+ representing hypo-, normo-, and hyper-kalaemia, respectively); ii) variation in extracellular magnesium (0.5/1/2 mM Mg2+ representing hypo-, normo-, and hyper-magnesemia, respectively); iii) pH (pH 7.4, 7 and 6.5 representing normal, acidosis and severe acidosis, respectively); and iv) temperature (37 °C and 42 °C representing physiological and febrile temperature). Hypokalaemia significantly increased potency of hERG block for both chloroquine and hydroxychloroquine (1.4- and 2.0-fold increase, respectively) while hyperkalaemia significantly decreased potency of chloroquine (2.1-fold decrease). Azithromycin was insensitive to kalaemic variation (Figure 2, Table 1). Hypomagnesemia had no significant effect on potency of any of the drugs. However, hypermagnesemia significantly increased potency of hERG block for both chloroquine and hydroxychloroquine (2.8-fold and 1.3-fold respectively (Figure 2, Table 1)). Reduction in pH from 7.4 to 7 significantly decreased potency of all drugs (3.4-, 5.0- and 2.2-fold for chloroquine, hydroxychloroquine, and azithromycin respectively) and this trend continued with further reductions in potency observed at pH 6.5 (Figure 2, Table 1). Finally, increased temperature (42 °C) significantly decreased potency of chloroquine and hydroxychloroquine by 1.9- and 1.6-fold respectively, but increased potency of azithromycin by 3.9-fold (Figure 2, Table 1).