title: Relation of amiodarone hepatic and pulmonary toxicity to serum drug concentrations and superoxide dismutase activity.
abstract: Hepatic enzymes, pulmonary function, serum amiodarone and desethylamiodarone (DEA) concentrations and erythrocyte superoxide dismutase (SOD) activity were monitored at regular intervals for 1 year in 30 patients receiving amiodarone. Subclinical hepatotoxicity developed in 5 patients. These patients had higher baseline alanine transaminase values (42.6 +/- 6.8 vs 22.9 +/- 1.8 U/liter) and had an increase in serum aspartate transaminase from 27 +/- 4.1 at baseline to 147 +/- 77.3 U/liter at 12 months. The other patients had little variation in aspartate transaminase. Six patients with normal baseline carbon monoxide diffusing capacity had subclinical pulmonary toxicity develop with a mean decrease in diffusing capacity to 0.7 +/- 0.05 of the baseline value, which correlated with decreasing erythrocyte SOD activity. Mean carbon monoxide diffusing capacity and SOD activity remained unchanged in the other patients. The mechanisms of hepatic and pulmonary injury remain unknown, but appear to be associated with exposure to higher total serum concentrations of amiodarone plus DEA. Patients who had hepatic and/or pulmonary abnormalities develop received higher doses of amiodarone (440 +/- 27 vs 340 +/- 18 mg/day), but also had a higher amiodarone:DEA ratio suggesting that dose-dependent kinetics contributed to the higher concentrations. Elevated baseline alanine transaminase may indicate increased risk for hepatotoxicity while a progressive decrease in erythrocyte SOD may be an early indication of pulmonary toxicity. The latter finding indicates a need to investigate the role of free radicals in the pathogenesis of amiodarone pulmonary toxicity.
authors.affiliation: Department of Medicine, University Hospital, University of Western Ontario, London, Canada.
authors.forename: P T
authors.initials: PT
authors.lastname: Pollak
authors.forename: A D
authors.initials: AD
authors.lastname: Sharma
authors.forename: S G
authors.initials: SG
authors.lastname: Carruthers
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000638:Amiodarone / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D004796:Clinical Enzyme Tests; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000175:diagnosis; D008171:Lung Diseases / Q000139:chemically induced* / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D011653:Pulmonary Diffusing Capacity; D013482:Superoxide Dismutase / Q000097:blood*
chemical_list: D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C036116:desethylamiodarone; D000638:Amiodarone