Disposition of amiodarone and its proximate metabolite, desethylamiodarone, in the dog for oral administration of single-dose and short-term drug regimens.
A comparative study of the plasma disposition and tissue distribution of amiodarone and its proximate metabolite, desethylamiodarone, for a single oral dose and short-term oral dosage regimens was conducted in the dog. Four groups of male mongrel dogs (six per group) received one of the following oral dosage regimens: single dose of 40 mg amiodarone/kg; 40 mg amiodarone/kg/day for 10 days and then 30 mg/kg/day for 4 days; 40 mg amiodarone/kg/day for 10 days, 30 mg/kg/day for 4 days, and then no treatment for 14 days; and 40 mg amiodarone/kg/day for 10 days, 30 mg/kg/day for 4 days, and then 20 mg/kg/day for 5 days/week for 2 weeks. The plasma and tissue amiodarone and desethylamiodarone concentrations were determined by HPLC. The plasma concentration of amiodarone was greater than that of desethylamiodarone for the four dosage regimens. The apparent plasma elimination half-life of amiodarone was prolonged following repeated drug administration (3.2 days) compared with a single drug dose (7.5 hr). There was extensive extravascular distribution of amiodarone and desethylamiodarone resulting in progressive tissue accumulation of drug and metabolite for the short-term regimens. For most of the dosage regimens, the concentration of amiodarone was greater than that of desethylamiodarone in left and right ventricles, thyroid gland, adipose tissue, and kidney, whereas the parent drug and metabolite concentrations were similar in lung, liver, and brain. There was predominant accumulation of amiodarone in adipose tissue and desethylamiodarone in lung. After cessation of amiodarone administration, there was rapid elimination of parent drug and metabolite from all tissues, except for amiodarone from adipose tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Brien, JF; Jimmo, S; Brennan, FJ; Armstrong, PW; Abdollah, H
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