© 1997 Oxford University Press
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Cardiovascular Effects after Inhalation of Large Doses of Albuterol Dry Powder in Rats, Monkeys, and Dogs: A Species Comparison
*Drug Safery and Metabolism, Schering-Plough Research institute P.O. Box 32, 144 Route 94, Lafayette, New Jersey 07848, Canada
ClinTrials BioResearch Ltd. Montreal, Quebec, Canada
Received December 16, 1996; accepted September 3, 1997
Albuterol is a quickly acting ß2-adrenergic agonist bronchodilator widely used by asthmatics. Because recent case-control studies have suggested a relationship between the increase in mortality of asthmatics over the past decade and the use of ß2-adrenergic agonists in the control of asthma, concern has developed regarding the potential cardiotoxicity of ß2-specific adrenergic agonists, including albuterol. The aim of this investigation was to assess the potential for cardiotoxicity of inhaled albuterol dry powder in rats, monkeys, and dogs. 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 filtered conditioned air and handled in the same manner as the albuterol-exposed animals. Plasma concentrations of albuterol confirmed systemic exposure. The daily inhaled dose received by the animals was calculated based on measured respiratory minute volumes, published respiratory tract deposition data, as well as HPLC-determined particle size distribution data and aerosolized albuterol concentrations Multiples of the maximum daily clinical dose (presentation of 15 µg/kg in a 70-kg human) were approximately 0.25- to 2500-fold in the rat, 9- to 100-fold in the monkey, and 0.5- to 90-fold in the dog. No findings attributed to albuterol were observed in the monkey. Tachycardia and transient hypokalemia occurred in rats at multiples of 1.5 times or greater of the maximum clinical dose. Absolute and relative heart weights increased in rats receiving multiples of 47 times or greater of the maximum human 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 occurred at all doses tested. Slight to mild fibrosis in the papillary muscles of the left ventricle of the heart occurred in dogs at multiples 
19 times the clinical dose. The cardiovascular effects observed were consistent with the known pharmacologic action of ß2 agonists. Due to the lack of toxicologically relevant findings in rats and monkeys and the wide safety margin in dogs, the findings in this study do not suggest a cardiotoxicity risk in the human population alter repeated exposures to clinical doses of albuterol currently used in the treatment of asthma.