Effect of amiodarone on the disposition of acetaminophen in the rat.
Amiodarone has been demonstrated to form a cytochrome P-450Fe(II):metabolite complex. The administration of other agents which form this type of complex, such as troleandomycin, has been shown to deplete hepatic glutathione content. Depletion of glutathione will result in an increased synthesis of glutathione and an increased utilization of cysteine. Since inorganic sulfate and glutathione share cysteine as a common precursor, we postulated that amiodarone pretreatment may reduce the sulfation of drugs. To test this hypothesis, the effect of amiodarone pretreatment on acetaminophen disposition was examined in the rat. Acetaminophen (150 mg/kg) was administered to rats pretreated with amiodarone hydrochloride (100 mg/kg/d) or diluent for 5 d. There were no significant differences in the urinary recovery of acetaminophen sulfate or the partial clearance of acetaminophen to the sulfate metabolite between control and amiodarone-pretreated animals. There was a trend toward an increased urinary recovery of acetaminophen glucuronide in animals pretreated with amiodarone, but this did not reach statistical significance. Amiodarone pretreatment had no effect on the renal clearances of acetaminophen or its metabolites. These results suggest that amiodarone pretreatment does not alter the sulfation of drugs and that the formation of an amiodarone P-450Fe(II):metabolite complex is quantitatively insignificant.
Svensson
C K
CK
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI 48202.
Chong
M T
MT
D000082:Acetaminophen / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D005965:Glucuronates / Q000097:blood / Q000652:urine; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000097:blood / Q000652:urine
D005965:Glucuronates; D013431:Sulfates; D000082:Acetaminophen; D000638:Amiodarone