Influence of hepatic P450‐mediated Amiodarone metabolism on Amiodarone‐induced pulmonary toxicity

Abstract

Amiodarone (AMI), a widely used, effective anti‐arrhythmic drug, has severe side effects, including acute lung toxicity and pulmonary fibrosis. Our aim is to test the hypothesis that a decline in liver microsomal P450‐meditated AMI metabolism leads to increased accumulation of AMI in lung and consequently greater pulmonary toxicity. We studied three mouse strains, all on B6 background: wild type (WT), LCN (liver‐specific P450 reductase (CPR) null; has little P450 activity in hepatocytes), and Cpr‐low (has global suppression of CPR expression in all cells). Adult, male mice were treated with AMI (160 mg/kg, i.p.) or vehicle alone, once/day for 3 days. On day 4, tissue AMI levels were determined, and bronchoalveolar lavage (BAL) was analyzed for signs of lung toxicity. Hepatic AMI levels were 1.1‐and 2.7‐fold higher, whereas lung AMI levels were 1.3‐and 4.3‐fold higher, in Cpr‐low and LCN mice, respectively, than in WT mice. As a general marker of lung toxicity, total numbers of cells in BAL were increased by 1.7‐and 2.3‐fold, in Cpr‐low and LCN mice, respectively, compared to treated WT mice. Furthermore, a 2‐fold increase in the number of lymphocytes in BAL was seen in LCN, compared to WT, following AMI treatment. These results support a role of liver P450 in protecting the lung against AMI's acute toxicity. Studies are ongoing to determine if a decrease in hepatic AMI metabolism leads to greater rate of pulmonary fibrosis.