hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 172

general approaches are considered to minimize the QT prolongation associated
with drug interaction. Combinations of drugs such as two drugs from Class I (PD
interaction) quinidine plus dofetilide or a Class I drug plus a Class II drug when
there is also a PK interaction (PD plus PK), for example quinidine with thioridazine
should be avoided. The combinations can be recommended when benefit outweighs
the risk, a Class I drug plus Class II drug when there is no PK interaction (PD only)
e.g., procainamide with cisapride. Within Class II drugs when there is also a PK
interaction (PD plus PK) such as erythromycin with cisapride should be avoided.
Class II drugs when there is no PK interaction (PD only) e.g., amitriptyline plus
cisapride combinations of Class III drugs may result in increased QT prolongation
should be avoided. Patients with pre-existing QT prolongation, prolonged baseline
QT, abnormally prolonged QT interval, QTc during drug and T-wave lability
changes during drug treatment are probably at increased risk of developing arrhy-
thmias. Patients with the risk factors including bradycardia, female sex, genetics
(gene mutations in cardiac ion transport), heart disease (heart failure, ischemia),
electrolyte disturbances (hypocalcemia, hypokalemia, hypomagnesemia and hypo-
thyroidism) cardiac hypertrophy and increased age should be monitored carefully
and therapy with alternative agents posing no risk for delayed repolarization should
be considered [ 60 - 62 ]. Terfenadine and ketoconazole are most widely used positive
reference drugs in non-clinical cardiac repolarization safety studies. Study reports
have suggested the effects of terfenadine, ketoconazole alone and their combina-
tion on QT prolongation using conscious guinea pigs and QT were recorded using
a telemetry system. Neither terfenadine nor ketoconazole produced any effect on
the respiratory rate (RR), QT intervals, heart rate (HR). However, a combination
of terfenadine and ketoconazole significantly prolonged RR and QT intervals
and decreased HR in a time-dependent manner [ 63 ].
4.1 hERG Activators
RPR260243: (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-
trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid), is a novel activator
of hERG . By using patch-clamp electrophysiology, it dramatically slowed cur-
rent deactivation when applied to cells which were stably expressing hERG
(Table 1 )[ 58 ].
PD-118057: After RPR260243, another potent hERG channel enhancers i.e.,
2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid (PD-118057)
was reported, which increases the peak tail hERG current in human embryonic
kidney cells [ 59 ]. PD-118057 did not affect the voltage dependence and kinetics of
gating parameters, nor did it require open conformation of the channel. In isolated
guinea pig cardiomyocytes, PD-118057 showed no major effect on I Na ,I Ca and I K .
PD-118057 shortened the action potential duration and QT interval in arterially
perfused rabbit ventricular wedge preparation in a concentration-dependent manner
(Table 1 ).