Pharmacology and Pharmacokinetics of Amiodarone

Freedman, Michael D.; Somberg, John C.

doi:10.1002/j.1552-4604.1991.tb03673.x

Cited by 112 publications

(48 citation statements)

References 55 publications

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“…It was reported that amiodarone could undergo extensive enterohepatic circulation (Freedman and Somberg, 1991;Roden, 1993). Glucuronidation of the metabolites and biliary excretion was thought to be the final elimination process for amiodarone (Freedman and Somberg, 1991). However, the phase II metabolism of amiodarone had not been comprehensively studied, although there is indirect evidence (after hydrolysis) for glucuronide metabolites of amiodarone in human plasma (Ha et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…However, the deiodination of amiodarone is still unclear and is a topic of considerable debate. A previous study proposed that deiodination was one of the metabolic pathways of amiodarone in humans (Freedman andSomberg, 1991), andYoung andMehendale (1986) reported that MDEA could be dideiodinated in rabbit liver microsomes. However, others claimed that no deiodinated metabolites could be found in vivo and in vitro (Ha et al, 2001a(Ha et al, , 2005.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…In mammals, MDEA could be transformed to 3Ј-hydroxyl MDEA both in vivo and in vitro (Ha et al, 1996(Ha et al, , 2001a(Ha et al, ,b, 2005, and 3Ј-hydroxylation was regarded as a primary metabolite of MDEA in humans (Ha et al, 2005). Further dealkylation and deamination of MDEA could result in low amounts of DDEA and DAA in human plasma (Freedman and Somberg, 1991;Ha et al, 2005). In human urine, only negligible amounts of amiodarone and MDEA were detectable after oral drug dosing (Harris et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

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Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

Deng

You²,

Chen³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Amiodarone is recognized as an effective drug in the treatment of arrhythmias. Previous experiments demonstrated that mono-Ndesethylamiodarone (MDEA) was the major circulating metabolite in humans. In addition, dealkylation, hydroxylation, and deamination were minor metabolic pathways. The purpose of this study was to identify the metabolites of amiodarone in the bile obtained from patients with T-tube drainage after oral drug administration. Amiodarone metabolism in vitro was also investigated using human liver microsomes (HLMs) and S9 fraction. Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS) revealed 33 metabolites in human bile, including 22 phase I and 11 phase II metabolites. The major metabolites were MDEA (M7) and -carboxylate amiodarone (M12). Metabolite M12 was isolated from human bile, and the chemical structure was confirmed using UPLC-Q/TOF MS and 1 H NMR.Moreover, the authentic standards of two hydroxylated metabolites, 2-hydroxylamiodarone and 3-hydroxylamiodarone, were obtained through microbial transformation. Several novel metabolic pathways of amiodarone in human were proposed, including -carboxylation, deiodination, and glucuronidation. The in vitro study demonstrated that incubation of HLMs with amiodarone did not give rise to any carboxyl metabolites. In contrast, M12 and its metabolites were detected in human liver S9 incubation samples, and the production of these metabolites were inhibited almost completely by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, suggesting the involvement of alcohol dehydrogenase in the -carboxylation of amiodarone. Overall, UPLC-Q/TOF MS analysis leads to the discovery of several novel amiodarone metabolites in human bile and underscores the importance of bile as an excretion pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

Deng

You²,

Chen³

et al. 2011

Drug Metab Dispos

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“…This might be due to enterohepatic recirculation of CRA13 because drugs subject to enterohepatic recirculation are often characterized by multiple peaks and a long half-life (e.g., estradiol) (Vree and Timmer, 1998). Likewise, compounds of many other classes such as sulfonamide diuretics (Vree and van der Ven, 1999), antiarrhythmic drugs (Freedman and Somberg, 1991), or nonsteroidal anti-inflammatory drugs (Busch et al, 1995) are also subjected to enterohepatic recirculation. In addition, the bile salts, released after meal ingestion, could have facilitated further dissolution and solubilization of CRA13 [solubility in water, ϳ0.001-0.002 mg/ml; log partition coefficient (log P) ϭ 6.9], allowing a second absorption phase.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptor Agonist 13, a Novel Cannabinoid Agonist: First in Human Pharmacokinetics and Safety

Gardin¹,

Kucher²,

Kiese³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB 1 and CB 2 receptors. This phase I study aimed to evaluate the pharmacokinetics, safety, and tolerability of single oral doses of CRA13. Sixty-three of 69 healthy adult males were randomized in seven cohorts (n ‫؍‬ 9) to receive 1 to 80 mg of CRA13 or placebo orally in fasted condition. To investigate the diet effect, an independent group (n ‫؍‬ 6) was randomized to receive 40 mg of CRA13 after high-fat and high-calorie breakfast in crossover design with a 2-week washout period. Peak plasma concentration (C max ) ranged from 7.8 to 467.6 ng/ml (1-80 mg). CRA13 was rapidly absorbed and demonstrated linear pharmacokinetics (1-80 mg). Time to reach C max (t max ) was 1.5 to 2 h for all doses in both fasted and fed groups. Administration of 40 mg of CRA13 with food induced approximately 2-fold increase in the C max and the area under the concentration-time curve, AUC 0 ؊ tz . The apparent elimination half-life (t 1/2 ) was 21 to 36 h and 30 to 41 h for fasted and fed groups, respectively. Dizziness, headache, and nausea were the most frequently reported adverse events (AEs), predominantly at the 40-and 80-mg doses. The incidence of AEs was dose-dependent and mild to moderate. No deaths and serious adverse events were reported. In conclusion, CRA13 was reasonably well tolerated and demonstrated a linear pharmacokinetics over the studied dose range (1-80 mg). Food intake increased CRA13 C max and AUC 0 ؊ tz by approximately 2-fold, whereas t max was unaffected.Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB 1 and CB 2 receptors (Dziadulewicz et al., 2007). Cannabis extracts contain a mixture of psychoactive, highly brain-penetrant cannabinoids, structurally related to the major active constituent ⌬ 9 -tetrahydrocannabinol (Fig. 1). In animals, cannabinoids are known to produce a range of well established effects including analgesia, catalepsy, reduced locomotor activity, and hypothermia. These effects are mediated through the activation of CB 1 and CB 2 receptors, both of which are G-protein-coupled and exert their effects predominantly via inhibition of adenylate cyclase (Pertwee and Ross, 2002). Published literature indicates that CB agonists may also be effective against persistent nociceptive processes in clinical conditions associated with chronic pain states (Richardson, 2000;Fox et al., 2001;Pertwee, 2001; Rice, 2001;Karst et al., 2003;Notcutt et al., 2004;Svendsen et al., 2004).Selective activation of peripheral CB 1 receptors could evolve as a valuable therapy for chronic pain conditions as long as the central nervous system (CNS) effects are suppressed. CRA13, in behavioral animal models (rat and guinea pig) of chronic pain (neuropathic and nociceptive), was able to reverse established mechanical hyperalgesia after both oral administration and local injection into h...

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Thyroid Disease and Pregnancy

Girling¹

2002

Medical Disorders in Obstetric Practice

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Pharmacology and Pharmacokinetics of Amiodarone

Cited by 112 publications

References 55 publications

Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

Identification of Amiodarone Metabolites in Human Bile by Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

Cannabinoid Receptor Agonist 13, a Novel Cannabinoid Agonist: First in Human Pharmacokinetics and Safety

Thyroid Disease and Pregnancy

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