CARDIOVASCULAR EFFECTS AFTER INHALATION OF LARGE DOSES OF ALBUTEROL DRY POWDER IN RATS, MONKEYS, AND DOGS - A SPECIES COMPARISON

Albuterol is a quickly acting beta(2)-adrenergic agonist bronchodilato r widely used by asthmatics. Because recent case-central studies have suggested a relationship between the increase in mortality of asthmati cs over the past decade and the use of beta(2)-adrenergic agonists in the control of asthma, concern has developed regarding the potential c ardiotoxicity of beta(2)-specific adrenergic agonists, including albut erol. The aim of this investigation was to assess the potential for ca rdiotoxicity of inhaled albuterol dry powder in rats, monkeys, and dog s. All species were exposed to an aerosol of albuterol 1 h per day, 7 days per week, for at least 2 weeks. Control groups were exposed to fi ltered conditioned air and handled in the same manner as the albuterol -exposed animals. Plasma concentrations of albuterol confirmed systemi c exposure. The daily inhaled dose received by the animals was calcula ted based on measured respiratory minute volumes, published respirator y tract deposition data, as well as HPLC-determined particle size dist ribution data and aerosolized albuterol concentrations. Multiples of t he maximum daily clinical dose (presentation of 15 mu g/kg in a 70-kg human) were approximately 0.25- to 2500-fold in the rat, 9- to 100-fol d in the monkey, and 0.5- to 90-fold in the dog. No findings attribute d to albuterol were observed in the monkey. Tachycardia and transient hypokalemia occurred in rats at multiples of 1.5 times or greater of t he maximum clinical dose. Absolute and relative heart weights increase d in rats receiving multiples of 47 times or greater of the maximum hu man dose. In the absence of histopathologic findings, the increases in rat heart weights were considered a physiologic hypertrophic response to tachycardia. In dogs tachycardia and transient hypokalemia occurre d at all doses tested. Slight to mild fibrosis in the papillary muscle s of the left ventricle of the heart occurred in dogs at multiples gre ater than or equal to 19 times the clinical dose. The cardiovascular e ffects observed were consistent with the known pharmacologic action of beta(2)-adrenergic agonists. Due to the lack of toxicologically relev ant findings in rats and monkeys and the wide safety margin in dogs, t he findings in this study do not suggest a cardiotoxicity risk in the human population after repeated exposures to clinical doses of albuter ol currently used in the treatment of asthma. (C) 1997 Society of Toxi cology.