The Teratogenic Effect of Dofetilide during Rat Limb Development and Association with Drug‐Induced Bradycardia and Hypoxia in the Embryo

Abstract

Drugs that induce periods of bradycardia and/or arrhythmia of the embryonic heart and cause the embryo to become hypoxic are potential human teratogens.

Early Gestational Hypoxia and Adverse Developmental Outcomes

“…The class III antiarrhythmics, dofetilide, amiodarone, and sotalol, have been tested in vitro using whole rat embryos inducing a dose‐related bradycardia (Spence et al, ; Webster et al, ; Danielsson et al, ; Abela et al, ; Ritchie et al, , ). During preclinical testing, these drugs caused limb defects, including adactyly and an increased incidence of embryonic death when administered to pregnant rats during a sensitive window of development (Fig.…”

“…Other malformations included maxillary hypoplasia, open eyes, ventricular septal defects (VSDs), and other cardiovascular defects (GD 10–13) (Skold et al, ). Localized hemorrhage and hypoxia preceded the limb malformations (Webster et al, ; Ritchie et al, , ). By GD 15, the rat embryo is no longer dependent on IKr and even very high doses of dofetilide or almokalant were without effect (Webster et al, ).…”

The effect of dofetilide on embryonic heart rate of rat embryos during early development using high-resolution ultrasound

“…The mechanism of action is unknown but previous in vitro studies have known that dofetilide causes a concentrationdependent slowing of the GD11 rat embryonic heart in vitro [2]. On GD13, it was shown that embryonic bradycardia was associated with hypoxia in the rat embryo [3]. The aim of this study was to test the hypothesis that a teratogenic dose of dofetilide administered on GD11 in the rat would induce embryonic bradycardia and arrhythmia in vivo with full recovery within 24 h.…”

A comparison of drug-induced cardiotoxicity in rat embryos cultured in human serum or protein free media

“…An example is the antiarrhythmic drug dofetilide which blocks the hERG potassium ion channel. If the drug is administered to a pregnant rat during the organogenic period it causes bradycardia and arrhythmia of the embryonic heart without any adverse effects to the dam (Ritchie, Ababneh, Oakes, Power, & Webster, 2013). The resultant circulation disturbances and hypoxia in the embryo are responsible for the congenital malformations observed at term.…”

“…For each drug we determined the concentration that caused severe bradycardia down to the no-effect concentration. This methodology clearly identified these drugs as potential hazards for human pregnancy since unwanted embryonic bradycardia can potentially lead to growth retardation, malformation and/ or embryonic death (Ritchie et al, 2013;Webster & Abela, 2007).…”