Teratogenic potential of almokalant, dofetilide, andd-sotalol: Drugs with potassium channel blocking activity

Abstract

Drugs with class III antiarrhythmic activity are potential human teratogens because of their ability to cause bradycardia in the embryo during the organogenic period. Three drugs with class III antiarrhythmic activity, almokalant, dofetilide and d‐sotalol, were compared in vitro using rat embryo culture. Each of these drugs caused a concentration‐dependent bradycardia in 11‐ or 13‐day rat embryos. For each drug the effective concentration was considerably greater than the human therapeutic 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 caused increased resorptions and the same stage‐dependent malformations. Dosing on gestational day (GD) 11 was associated with right‐sided oblique 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 the proposed pathogenesis that the drug‐induced bradycardia caused embryonic hypoxia/ischemia. This study indicates that the induction of malformations/embryonic death by class III antiarrhythmic drugs which inhibit lkr is a class effect secondary to a common pharmacological action on the embryonic heart. © 1996 Wiley‐Liss, Inc.

Developmental Toxicity in the Pregnant Rabbit by theClass III Antiarrhythmic Drug Sotalol

“…Developmental toxicity occurred at doses causing no adverse effects in the mothers, with the exception of the two deaths that will be discussed later in this section. The observed sotalol-induced embryonic death in this study is in accordance with what has been shown for other Ikr blockers in studies in rats (Ban et al 1994;Spence et al 1994;Marks & Terry 1996;Webster et al 1996) and in mice (Skö ld & Danielsson, 2000). Single-dose administration during Day 9, 10, 11, 12, 13, or 14 of the selective Ikr blockers dofetilide and almokalant in rats (Spence et al 1994;Webster et al 1996) resulted in embryonic death.…”

“…In rodent embryos cultured in vitro during the susceptible period, a dose-dependent occurrence of embryonic bradycardia, arrhythmia and cardiac arrest has been noticed for almokalant and dofetilide (Spence et al 1994;Webster et al 1996) and L-691,121 (Ban et al 1994). The results in these in vivo and in vitro studies show a very good correlation between maternal concentrations, which were related with embryonic death, and concentrations that caused severe dysrhythmia.…”

“…This is also in accordance with what has been reported from rat studies in which the highest incidence of embryonic death was obtained Days 12-13 when the same dose was given. Embryonic death started to occur on Day 9 (Webster et al 1996), while no increased mortality was seen on Day 8. These data suggest that Ikr channels are expressed and functional when the embryonic heart starts beating, which occurs on Day 9.6 in the rat (Ban et al 1994).…”

“…Administration during other days within the susceptible period (Days 9-14) with the same dose did not increase the incidences of embryonic death. The doses had to be increased considerably during these days in order to obtain the same high incidence of embryonic death (Ban et al 1994;Webster et al 1996).…”

“…Embryos cultured in vitro during this period show dose-dependent bradycardia, arrhythmia and cardiac arrest after exposure to almokalant, dofetilide and L-691,121 (Spence et al 1994;Webster et al 1996). Pharmacologically induced embryonic bradycardia and arrhythmia have been proposed to be the underlying mechanism for developmental toxicity observed after administration of these agents in vivo in rodents (Abrahamsson et al 1994;Webster et al 1996;Skö ld & Danielsson 2000). The developmental toxic effects are mainly manifested as embryonic death, but also hypoxia-related external malformations are reported in foetuses surviving hypoxic episodes due to arrhythmia in early embryonic development.…”