Susceptibility to amiodarone-induced pulmonary toxicity: relationship to the uptake of amiodarone by isolated lung cells.
In previous studies, we showed that Fischer rats fed 175 mg/kg of amiodarone accumulated large amounts of drug and metabolite in the lung and developed pulmonary toxicity, whereas Wistar rats fed the same drug dose had significantly less amiodarone in the lung and did not develop pulmonary inflammation. The present study was designed to determine whether this difference in susceptibility between the strains was related to differences in uptake of amiodarone by lung cells. We found that isolated mixed lung cells of Fischer rats sequester significantly more drug than cells from Wistar rats. This difference in uptake cannot be due to drug metabolism because the lung is not capable of metabolizing amiodarone. We also found that the alveolar macrophage is one of the cell types in the mixed cell population that is partially responsible for the difference in drug uptake and that fibroblasts and type II pneumocytes are not involved. In addition, despite the fact that there was no difference in drug uptake, we found that fibroblasts isolated from Fischer rats were more susceptible to amiodarone-induced cytotoxicity than were Wistar fibroblasts. We conclude that genetic differences in lung drug sequestration and possibly the sensitivity to cytotoxicity may explain differences in susceptibility to amiodarone-induced pulmonary toxicity.
Wilson
B D
BD
Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA.
Lippmann
M L
ML
D000638:Amiodarone / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008171:Lung Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar
D000889:Anti-Arrhythmia Agents; D000638:Amiodarone