The effect of beta-naphthoflavone on the metabolism of amiodarone by hepatic and extra-hepatic microsomes.
Amiodarone is a potent antiarrhythmic drug with several limiting side effects, some of which have been correlated with increased levels of its more toxic metabolite, desethylamiodarone. Elevated serum desethylamiodarone to amiodarone ratios are associated with a risk of amiodarone-induced pulmonary toxicity. Polycyclic aromatic hydrocarbons such as beta-naphthoflavone are known to increase desethylamiodarone levels in rat in vivo. In this article we investigated if this increase was solely due to increased formation as a result of cytochrome P450 (CYP) 1A1 and 1A2 induction in different rat hepatic and extra-hepatic tissues. Additionally, the effect of amiodarone treatment on CYP1A1 and 1A2 gene expression and activity was investigated. In rats, beta-naphthoflavone was found to increase desethylamiodarone forming activity in lung and kidney microsomes. Amiodarone increased beta-naphthoflavone mediated induction of CYP1A1 gene expression in liver, lung and kidney. However, there was no significant change in CYP1A activity. As expected, the data indicated that the increase in desethylamiodarone levels in vivo was partly due to increased formation through CYP1A1 induction, although increased formation was only evident in some extra-hepatic tissues. Amiodarone treatment did not affect basal or induced CYP1A activity.
Elsherbiny
Marwa E
ME
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
El-Kadi
Ayman O S
AO
Brocks
Dion R
DR
D000638:Amiodarone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019324:beta-Naphthoflavone / Q000633:toxicity*
D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C036116:desethylamiodarone; D000638:Amiodarone