Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 38, Issue 5, Pages 737-744Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00005344-200111000-00010
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Funding
- NHLBI NIH HHS [HL49989, HL46681] Funding Source: Medline
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The long QT-related arrhythmia torsades de pointes (TdP) can arise with mutations in HERG and during treatment with drugs that block cardiac I-Kr, the current encoded by HERG. Multiple test systems have been used to assess drug block of I-Kr. This study evaluated the I-Kr blocking potency of a series of antiarrhythmics associated with a range of clinical risks of TdP in two such systems: mouse AT-1 cells (in which I-Kr is the major repolarizing current) and Ltk cells transiently transfected with HERG (n = 4-10 cells per drug). For each compound, the concentration required to produce 50% block of I-Kr or HERG tail currents (IC50) was determined. There was an excellent correlation (r = 0.98, p < 10(-5)) between values obtained in the two systems. However, the relation between the liability of a drug to cause TdP appeared dissociated from I-Kr blocking potency. Quinidine, dofetilide, ibutilide, procainamide, and disopyramide are all associated with TdP, but only the first three were potent blockers (IC50 less than or equal to 1 muM), whereas procainamide and disopyramide were not (IC50 > 50 muM). Conversely, verapamil and amiodarone, drugs not associated with TdP were also blockers (IC50 less than or equal to 1 muM). We conclude that I-Kr blocking potency can be readily assessed in either AT-1 cells or systems in which HERG is heterologously expressed. However. not all drugs causing TdP are potent I-Kr blockers, and I-Kr block is not necessarily associated with TdP. Other properties of these drugs, therefore, contribute to their propensity to cause TdP.
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