Pharmacokinetics of Amiodarone in hyperlipidemic and simulated high fat‐meal rat models

The objective of this study was to examine the effect of a high fat meal and hyperlipidemia on the pharmacokinetic behavior of amiodarone. To evaluate these effects, single doses of amiodarone were administered to rats i.v. (25 mg/kg) or orally (50 mg/kg). Some rats were rendered hyperlipidemic by intraperitoneal doses of poloxamer 407 followed by amiodarone i.v. In other normolipidemic rats, amiodarone was administered i.v. in a fasted state or after the administration of 1% cholesterol in peanut oil. Amiodarone plasma concentrations were considerably (>11‐fold) increased in hyperlipidemia. Substantial decreases were noted in the clearance, volume of distribution and unbound fraction (11.6, 23 and 24.7‐fold, respectively) in plasma of hyperlipidemic rats. Oral lipid caused a significant increase in plasma AUC0−∞ (1.38‐fold) and a significant decrease in clearance (1.5‐fold) of amiodarone after intravenous doses. Oral consumption of 1% cholesterol in peanut oil significantly increased the plasma AUC (1.83‐fold) and bioavailability of amiodarone (1.31‐fold) after oral doses. In determining oral bioavailability of lipophilic drugs such as amiodarone in food effect studies, in addition to the increase in absorption of drugs, other factors such as a decrease in clearance due to increases in lipoprotein levels should be taken into account. Copyright © 2005 John Wiley & Sons, Ltd.