Bioavailability of amiodarone tablets administered with and without food in healthy subjects

Xu, Meng; Mojaverian, Parviz; Doedée, Marijo; Lin, Emil T.; Weinryb, Ira; Chiang, Soong T.; Kowey, Peter R.

doi:10.1016/s0002-9149(00)01396-5

Cited by 63 publications

(49 citation statements)

References 6 publications

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“…The terminal t 1/2 of AM in humans given repeated doses has been estimated to be much larger (>50 days) than what we and others have observed in rat, reflecting a larger V d and slower CL of the drug in humans [9,31]. In human subjects, the circulating concentrations of DEA are much higher than those in the rat.…”

Section: Discussionmentioning

confidence: 46%

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

Shayeganpour

Hamdy

Brocks

2008

Biopharm & Drug Disp

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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 (approximately 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.

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Section: Discussionmentioning

confidence: 46%

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

Shayeganpour

Hamdy

Brocks

2008

Biopharm & Drug Disp

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“…Our previously calculated high extraction ratio of AM reported in rat (Shayeganpour et al, 2005) incorporates both hepatic and extrahepatic elimination in other tissues such as intestine, lung, or kidney. Based on previous reports (Wyss et al, 1990;Shayeganpour et al, 2005), circulating DEA levels in the rat are much lower than those observed in human (Meng et al, 2001). This finding could be due to this pathway being of minor importance in the elimination of AM in the rat.…”

Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

“…In rat, the pharmacokinetics of AM are comparable to that of humans, although clearance was higher in rats (Shayeganpour et al, 2005). Humans and rats show different plasma levels of DEA after AM administration, with lower levels being reported in rats compared with humans (Wyss et al, 1990;Meng et al, 2001).In human liver microsomes, an important contribution of CYP3A4 and CYP2C8 isoforms has been demonstrated (Fabre et al, 1993;Trivier et al, 1993). In the human intestine, CYP3A4 is a predominant cytochrome P450 (P450) enzyme and plays a significant role in the first-pass metabolism of 50 to 70% of marketed drugs (Wacher et al, 1998).…”

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confidence: 99%

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Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Shayeganpour¹,

El‐Kadi²,

Brocks³

2005

Drug Metab Dispos

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ABSTRACT:In humans, cytochrome P450 3A (CYP3A4) is a major enzyme involved in the metabolism of amiodarone (AM) to its major metabolite, desethylamiodarone (DEA). In rat, a commonly used animal model, metabolism of AM has not been well studied. To determine whether DEA is formed by CYP3A isoenzymes in the rat, microsomal protein was harvested from liver and intestine of male Sprague-Dawley rats. The metabolism of AM in each tissue was assessed utilizing chemical and immunological inhibitors. Ketoconazole, a presumed inhibitor of CYP3A1/2, significantly inhibited formation of DEA by hepatic and intestinal microsomes. However, based on the DEA formation kinetics in both microsomal preparations, it appeared that more than one cytochrome P450 enzyme was involved in the process. Coincubation of AM with microsomes and anti-CYP3A2 confirmed the role of CYP3A2 in the metabolism of AM in liver. DEA was also formed by rat recombinant CYP1A1 and CYP3A1, and was inhibited by ketoconazole; hence the participation of these enzymes in the intestinal DEA formation is likely. However, anti-CYP2B1/2 or -CYP1A2 antibodies had no effect on DEA formation. In rats given oral or intravenous AM, oral ketoconazole caused significant increases in area under the concentration versus time curve (AUC) of oral and i.v. treated rats and greater than 50% decreases in the total body clearance and V dss of i.v. treated rats. Although low to undetectable concentrations of DEA were a limitation for determination of AUC of DEA in vivo, it was confirmed that ketoconazole could cause a significant increase in AM concentrations in rat.Amiodarone (AM) is an iodinated class III antiarrhythmic benzofuran derivative with extensive clinical usage (Trivier et al., 1993;Soyama et al., 2002) in the treatment of life-threatening ventricular and supraventricular arrhythmias (Naccarelli et al., 2000). AM undergoes extensive hepatic biotransformation (Trivier et al., 1993;Soyama et al., 2002). Among the five pathways involved in the metabolism of AM (N-deethylation, hydroxylation, O-dealkylation, deiodination, and glucuronidation), N-dealkylation is most important in humans (Trivier et al., 1993;Soyama et al., 2002). The dealkylated metabolite, desethylamiodarone (DEA) shares some of the pharmacological and toxicological properties of AM. For instance, some of the electrocardiographic changes observed after long-term therapy with AM might be related to DEA (Kharidia and Eddington, 1996;Kodama et al., 1999). In addition, both AM and DEA inhibit the intracellular conversion of thyroxine to triiodothyronine. This inhibition may be related to some cardiotoxic effects of AM such as bradycardia and reduced myocardial oxygen consumption, and may explain the hypothyroid-like condition observed after chronic administration of AM (Hudig et al., 1994;Kodama et al., 1999).AM possesses a very large pharmacokinetic volume of distribution (V d ) and extensive tissue distribution, and, in turn, a long terminal half-life (t 1/2 ) in rat and human plasma (Pollak et al., 2000;Shaye...

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“…Administration with food is also recommended because it significantly increases the rate and extent of amiodarone absorption. 24 The combination of amiodarone with the CYP3A4 substrate simvastatin has been associated with an increased risk of myositis 25 (Table 3). Conversely, this risk seems to be smaller when amiodarone is combined with pravastatin, which does not use the cytochrome P450 system for metabolism.…”

Section: Currently Available Antiarrhythmic Drugsmentioning

confidence: 99%

Antiarrhythmic Drug Therapy for Atrial Fibrillation

2012

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Bioavailability of amiodarone tablets administered with and without food in healthy subjects

Cited by 63 publications

References 6 publications

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

Pharmacokinetics of desethylamiodarone in the rat after its administration as the preformed metabolite, and after administration of amiodarone

Determination of the Enzyme(s) Involved in the Metabolism of Amiodarone in Liver and Intestine of Rat: The Contribution of Cytochrome P450 3a Isoforms

Antiarrhythmic Drug Therapy for Atrial Fibrillation

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