Formation of an inactive cytochrome P-450Fe(II)-metabolite complex after administration of amiodarone in rats, mice and hamsters.
Administration of amiodarone hydrochloride (50-150 mg/kg i.p. daily) to rats, mice or hamsters resulted in the in vivo formation of a cytochrome P-450Fe(II)-amiodarone metabolite complex absorbing at 453 nm, unable to bind CO and biologically inactive. In rats, the amount of complex present in hepatic microsomes was small 24 hr after administration of a single dose of amiodarone (100 mg/kg i.p.) but was increased 2.5-times by pretreatment with phenobarbital and 8-times by pretreatment with dexamethasone phosphate. In addition, the complex increased linearly with time as the doses of amiodarone were repeated daily. When both enhancing factors were combined (treatment for 3 days with both dexamethasone and amiodarone), the amount of complex present in liver microsomes reached 0.78 nmol/mg protein or 40% of total cytochrome P-450 in rats. In these rats, in vitro disruption of the complex with potassium ferricyanide suppressed its Soret peak at 453 nm, increased by 70% the CO-binding spectrum of dithionite-reduced microsomes, and restored several monooxygenase activities. The 453 nm-absorbing complex was also formed in vitro upon incubation of amiodarone or N-desethylamiodarone with NADPH, EDTA and microsomes from dexamethasone-treated rats. The formation of the complex was smaller with microsomes from phenobarbital-treated rats and was not detected with microsomes from control rats. We conclude that amiodarone forms an inactive cytochrome P-450Fe(II)-metabolite complex in rats, mice and hamsters.
D000638:Amiodarone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004227:Dithionite / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005296:Ferrous Compounds / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D001572:Benzofurans; D005296:Ferrous Compounds; D004227:Dithionite; D003907:Dexamethasone; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D010105:Oxygenases; C036116:desethylamiodarone; D000638:Amiodarone