TERATOGENIC POTENTIAL OF ALMOKALANT, DOFETILIDE, AND D-SOTALOL - DRUGS WITH POTASSIUM CHANNEL BLOCKING ACTIVITY

Drugs with class III antiarrhythmic activity are potential human terat ogens because of their ability to cause bradycardia in the embryo duri ng the organogenic period. Three drugs with class III antiarrhythmic a ctivity, almokalant, dofetilide and d-sotalol, were compared in vitro using rat embryo culture. Each of these drugs caused a concentration-d ependent bradycardia in 11- or 13-day rat embryos. For each drug the e ffective concentration was considerably greater than the human therape utic plasma concentration. The reproductive outcome was also compared in vivo in Sprague-Dawley rats by oral administration of almokalant or dofetilide on single days during the organogenic period. Both drugs c aused increased resorptions and the same stage-dependent malformations . Dosing on gestational day (GD) 11 was associated with right-sided ob lique cleft lip and short tail, while dosing on day 13 caused digital hypoplasia and/or amputation. Susceptibility to these drugs started on GD 9 when the embryonic heart starts beating and ended on GD 15. The malformations were preceded by hemorrhage; which is consistent with th e proposed pathogenesis that the drug-induced bradycardia caused embry onic hypoxia/ischemia. This study indicates that the induction of malf ormations/embryonic death by class III antiarrhythmic drugs which inhi bit Ikr is a class effect secondary to a common pharmacological action on the embryonic heart. (C) 1996 Wiley-Liss, Inc.