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Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone
Author(s) -
Shayeganpour Anooshirvan,
Hamdy Dalia A.,
Brocks Dion R.
Publication year - 2008
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.599
Subject(s) - pharmacokinetics , bioavailability , oral administration , metabolite , pharmacology , amiodarone , chemistry , active metabolite , volume of distribution , first pass effect , jugular vein , distribution (mathematics) , medicine , endocrinology , biochemistry , mathematical analysis , mathematics , atrial fibrillation
The pharmacokinetics of desethylamiodarone (DEA), the active metabolite of amiodarone (AM), were studied in the rat after administration of AM or preformed metabolite. Rats received 10 mg/kg of either intravenous or oral AM HCl or DEA base. Blood samples were obtained via a surgically implanted jugular vein cannula. Plasma concentrations were measured by a validated LC/MS method. In all AM treated rats, AM plasma concentrations greatly exceeded those of the formed DEA. The fraction of AM converted to DEA after i.v. administration was 14%. Amiodarone had a significantly lower (∼50%) clearance than DEA, although the volume of distribution and terminal phase half‐life did not differ significantly. The hepatic extraction ratio of DEA was 0.48, similar to that of AM (0.51). Oral AM demonstrated higher plasma AUC (5.6 fold) and higher C max (6.1 fold) than oral DEA and oral bioavailability of AM (46%) was greater than DEA (17%). The estimated fraction of the oral dose of AM converted to DEA was 4.5 fold higher than after i.v. administration, suggesting first‐pass formation of DEA from AM. Amiodarone and DEA differed in their pharmacokinetic characteristics mostly due to a higher CL of DEA. With oral dosing, AM appeared to undergo significant presystemic first‐pass metabolism within the intestinal tract. Copyright © 2007 John Wiley & Sons, Ltd.