Disposition of amiodarone in rats after single and multiple intraperitoneal doses

Abstract

The pharmacokinetics of amiodarone was studied after single and multiple dosing in two groups of male Wistar and Albino rats. The first group (40 rats) received a single intraperitoneal (i.p.) dose of amiodarone (100 mg/kg) and 4 rats sacrificed 1, 2, 4, 6, 12, 18, 24, 36, 48 and 72 hours post dosing. The second group (42 rats) received amiodarone (50 mg/kg, i.p. daily) for 5 days a week for 5 weeks and 6 rats were sacrificed at 1, 2, 3, 4, 5, 6 and 8 weeks. Rats of both groups were sampled for blood, heart, lung and fat and the concentrations of amiodarone in these samples were determined using High Performance Liquid Chromatography (HPLC). The elimination of amiodarone from plasma after single dose followed a biphasic pattern with a terminal half-life of 54.7+/-8.2 hours. The concentrations of amiodarone in the tissues were halved within 26.8, 34.9 and 37.45 hours in the heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat after single dose were 1.24 microg/ml, 1.73 microg/mg and 29.01 microg/mg, respectivelly. The concentrations of amiodarone after multiple dosing were halved within 8.4, 5.5, 6.4 and 9.8 days, for the plasma, heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat during multiple doses were 0.97 microg/ml, 1.41 microg/mg, 7.63 microg/mg and 65.01 microg/mg respectively. In conclusion, after multiple dosing, the elimination half-life of amiodarone and its fat contents were 3.7 and 2.8 times greater than that after single dosing. The excessive amount of amiodarone observed in fat tissues after multiple dosing is probably the reason for the prolonged elimination half-life. Based on the elimination half-lives data, the time to steady state is about two weeks and the drug should be withheld for less than a month if a patient required discontinuation because of serious adverse effects.

Involvement of thymus in amiodarone-treated autoimmune myocarditis in rats

“…However, its effective use is impeded by a number of side effects such as thyroid abnormalities [15,16] and pulmonary toxicity [17,18]. Najjar reported that the plasma concentration of amiodarone in the rat receiving an intraperitoneal injection of 50 mg/kg amiodarone daily for 5 days a week for 5 weeks is 0.97 μg/ml [19] and Heger et al reported that the therapeutic plasma concentration of amiodarone in patients given this drug ranges between 0.5 to 2.5 μg/ml or 0.7 to 3.5 μmol/l [20]. Based on these reports, we speculated that the plasma concentration of amiodarone in rats receiving an intraperitoneal injection of 25 mg/kg amiodarone for 10 days in previous studies by our laboratory is within or below the therapeutic plasma concentration range in patients, although we have not determined the concentration in rats.…”

KB130015, A New Amiodarone Derivative with Multiple Effects on Cardiac Ion Channels

“…The tissue accumulation of KB015 has not been determined. Amiodarone accumulates into various tissues, particularly in fat, where its concentration can be 30-100 times higher than plasma concentrations (13,60). Concentrations in cardiac tissue are also higher than plasma levels (13) and intravenous amiodarone causes a five-fold higher cardiac concentration relative to the plasma concentration within 2.5 min.…”

“…In contrast with drugs from other classes, amiodarone has no or little proarrhythmic action and does not increase mortality in high-risk patients. However, the clinical benefits of amiodarone are complicated by many undesirable non-cardiac side effects (10,25,59,69,80,90,91) and by a very slow elimination of the drug [half-life, 17-55 h after a single dose; 27-55 days after chronic treatment (61,66,85,96)]. Therefore, there has been a constant interest in synthesizing new molecules, based on a structural modification of amiodarone.…”

LC-MS Method for Determining Amiodarone and Desethylaminodarone in Rat Plasma Used in Endogenous Overdosing Conditions Following Lipolysis

“…The method presents a good accuracy (101.45% between-run and 98.57% within-run for DEA and 97.68% within-run and 104.76% between-run for AMI) and precision for both compounds (9.4% within-run and 11.12% between-run for AMI and 13.56% within-run and 14.23% between-run for DEA) ( Table I and II). LLOQ was set at 5 ng/ml plasma AMI and 2.5 ng/ml plasma DEA, therefore the LC-MS method developed for AMI and DEA determination in rat plasma presents a much lower LLOQ compared to methods already published in scientific literature [7,8,9].…”