title: Effects of macrolide antibiotics on rat embryonic heart function in vitro.
abstract: The Swedish Medical Product Agency (MPA) has listed erythromycin as a suggested human teratogen, causing cardiovascular malformations. It is further suggested that this may be a class effect of macrolide antibiotics. The proposed teratogenic mechanism is blockade of the human ether-á-go-go-related (hERG)/IKr current in the embryonic heart causing bradycardia and arrhythmia resulting in altered cardiac blood flow and/or embryonic hypoxia. To test this hypothesis, we examined the effect of three macrolide antibiotics on the function of the rat embryonic heart. Gestational day 13 rat embryos in vitro were exposed to erythromycin (25-500 μM), clarithromycin (25-500 μM), or azithromycin (100 μM to 1 mM) for 3 hr. The effect on the embryonic heart was monitored every hour. The results showed that erythromycin and clarithromycin caused a concentration-dependent bradycardia. Twenty-five micromolar was a no-effect concentration for erythromycin and was close to a no-effect concentration for clarithromycin. Azithromycin only caused significant bradycardia at 1 mM. Additional studies were performed with the embryos cultured at 40°C instead of 38°C, to mimic fever. The increased temperature increased the number of arrhythmias but did not worsen the drug-induced bradycardia. The results support the concept that erythromycin and clarithromycin can adversely affect the embryonic heart but only at concentrations well outside expected embryonic exposure in the human.
authors.affiliation: Drug Safety and Toxicology, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Mats F
authors.initials: MF
authors.lastname: Nilsson
authors.forename: William S
authors.initials: WS
authors.lastname: Webster
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000196:embryology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000196:embryology; D001919:Bradycardia / Q000139:chemically induced / Q000196:embryology; D017291:Clarithromycin / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D046149:Embryo Culture Techniques; D004917:Erythromycin / Q000009:adverse effects; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000196:embryology*; D018942:Macrolides / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D013723:Teratogens; D004917:Erythromycin; D017291:Clarithromycin
keywords: embryonic cardiac function; hERG/IKr-blocking drugs; macrolide antibiotics; teratogenicity