| The current work examined the effect of hyperlipidemia (HL) on the disposition and metabolism of amiodarone (AM), a first line agent in the treatment of tachyarrhythmia, in rat. The studies used systemic hyperlipidemic and simulated high fat meal rat models. For this purpose a modified preexisting HPLC assay was used, and a novel sensitive LC/MS method was developed. The latter enabled us to measure low levels of AM and desethylamiodarone (DEA), the active metabolite of AM, in biological specimens.;Tissue distribution studies suggested that the increase in plasma concentration of AM in HL did not lead to decreases in all of the tissues. Indeed, the influence of HL on AM distribution was not uniform, but rather tissue-specific. The changes in DEA tissue AUC as a result of HL were not always in line with those observed for AM.;HL also caused a decrease in the metabolism of AM to DEA in rat liver. The decrease in Clint was in line with the reduction in selective expression of some of the CYP isoforms known to be involved in the metabolism of AM in the rat. Involvement of some of these enzymes including CYP1A1 and CYP3A1/2, both of which are present in intestinal and hepatic microsomes of rats, was demonstrated using some chemical and immunoinhibition techniques.;Evaluation of the effect of oral lipid on the intestinal metabolism of AM to DEA was accomplished using an in vitro everted gut metabolism technique. Pretreatment of rats with peanut oil caused a decrease in metabolizing efficiency in the intestine.;Hyperlipidemia caused increases in the plasma levels of AM due to significant decreases in clearance, volume of distribution and unbound fraction of drug. Oral lipid caused a significant increase in plasma AUC and a significant decrease in clearance of AM after intravenous doses. This was accompanied by an increase in the oral bioavailability of drug. In vitro distribution of AM and DEA in normolipidemic (NL) and HL human and rat plasma fractions indicated that HL caused a major shift of AM and DEA from lipoprotein deficient (LPDP) fraction to triglyceride rich lipoprotein (TRL) fraction in both species. |
