Identification and quantitation of novel metabolites of amiodarone in plasma of treated patients
Introduction
Amiodarone, which was initially developed 40 years ago as an antianginal drug, is still considered as one of the most effective antiarrhythmic agents (Mason, 1987, Julian et al., 1997). However, amiodarone therapy is accompanied by a variety of severe adverse effects, including pulmonary toxicity (Heger et al., 1983, Marchlinski et al., 1982), hepatotoxicity (Rigas et al., 1986), and thyroid dysfunction (Dickstein et al., 1984). The incidence of undesired effects appears to be dose dependent (Heger et al., 1983, Hilleman et al., 1998). Since the metabolism of amiodarone is not fully documented, the relationship between undesired effects and amiodarone metabolite(s) is poorly understood. In the present research situation, it is known that, in mammals, amiodarone is dealkylated to mono-N-desethylamiodarone (MDEA) (Flanagan et al., 1982). This pharmacologically active metabolite was found in in vitro experiments (Ha et al., 1992, Trivier et al., 1993, Fabre et al., 1993). Recently, it was observed that in vitro MDEA may be further cleared by hydroxylation (Ha et al., 2001), dealkylation to di-N-desethylamiodarone (DDEA), and deamination to deaminated amiodarone (DAA) (Kozlik, 2003). Independently of this, it is well known that amiodarone and its derivatives are very lipophilic; they are largely stored in the organ tissues rather than abundantly present in blood circulation. Thus, investigation of amiodarone metabolites in organ tissues should be more informative; however, such a study is not possible in humans. An alternative for studying amiodarone metabolism in humans is to use a sensitive and selective analytical assay to investigate metabolites other than MDEA in the plasma of patients receiving amiodarone.
Section snippets
Chemicals
Amiodarone [2-n-butyl-3-(3,5-diiodo-4-β-diethylaminoethoxybenzoyl)benzofuran hydrochloride] hydrochloride and mono-N-desethylamiodarone [2-n-butyl-3-(3,5-diiodo-4-β-ethylaminoethoxybenzoyl)benzofuran] hydrochloride (MDEA·HCl) were a kind gift from Sanofi-Synthélabo Research Center, Montpellier, France. The amiodarone analogue 2-n-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran (B2) was synthesized in previous studies (Ha et al., 2000). Other reference compounds, such as deaminated amiodarone [2-
Qualitative and quantitative analysis of known amiodarone metabolites
Our primary investigations indicated that 90–95% of the three studied compounds — 3′OH-MDEA, DDE, and DAA — and the internal standard MOPAM may be extracted with isooctane:2-propanol (85:15). This mixture of organic solvents had been used previously for extracting amiodarone and its related compounds from biological samples at pH 5.4 (Heger et al., 1984). We optimized the extraction for our analytes and observed that at pH 7.4, the extraction efficacy of our studied compounds was quantitative,
Discussion
The main finding in this study was the positive detection in human plasma of three compounds, which have been observed in our previous in vitro experiments (Kozlik, 2003), using the HPLC–APCI-MS/MS assay. This cannot be the artifact of the experiments, because they were not detected in plasma of patients receiving amiodarone intravenously. Among the new metabolites, the concentration of 3′OH-MDEA was 140.0 ng ml−1 (range 37–357 ng ml−1) and corresponded to 12.0% (range 3.58–23.5%) of the plasma
Acknowledgement
The authors thank Aileen McAinsh, Ph.D., Nashville, TN, USA, for assistance in editing the manuscript.
References (25)
- et al.
Thyrotoxicosis induced by amiodarone, a new efficient antiarrhythmic drug with high iodine content
Am. J. Med. Sci.
(1984) - et al.
Tocainide conjugation in humans: novel biotransformation pathway for a primary amine
J. Pharm. Sci.
(1980) - et al.
Relationships between amiodarone dosage, drug concentrations, and adverse side effects
Am. Heart J.
(1983) - et al.
Plasma and red blood cell concentrations of amiodarone during chronic therapy
Am. J. Cardiol.
(1984) - et al.
Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT—European Myocardial Infarct Amiodarone Trial Investigators
Lancet
(1997) - et al.
Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy
Circulation
(1985) - et al.
Distribution of amiodarone and its metabolite, desethylamiodarone, in human tissues
Can. J. Physiol. Pharmacol.
(1987) - et al.
Recherches dans la serie des benzofurannes. XXXVII. Etude comparee du transit et du metabolisme de l’amiodarone chez diverses especes animales et chez l’homme. (Research on the benzofuran series. XXXVII. Comparative study of transit and metabolism of amiodarone in different species of animals and humans)
Arch. Int. Pharmacodyn. Ther.
(1969) - et al.
Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions
Drug Metab. Dispos.
(1993) - et al.
Identification and measurement of desethylamiodarone in blood plasma specimens from amiodarone-treated patients
J. Pharm. Pharmacol.
(1982)
Metabolism of amiodarone (part I): identification of a new hydroxylated metabolite of amiodarone
Drug Metab. Dispos.
Structure-effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination
Eur. J. Clin. Pharmacol.
Cited by (35)
Spatiotemporal pharmacometabolomics based on ambient mass spectrometry imaging to evaluate the metabolism and hepatotoxicity of amiodarone in HepG2 spheroids
2023, Journal of Pharmaceutical AnalysisDevelopment of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity
2016, Chemico-Biological InteractionsThe role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity
2016, Toxicology LettersCitation Excerpt :It may be helpful for the patient administered amiodarone to take precautions to avoid the activation of CYP 1A1 as a result of their use of such dietary supplements or other CYP 1A1 inducers, as this could potentially affect the metabolism of amiodarone and its cytotoxicity. Although amiodarone is metabolized primarily to mono-N-desethylamiodarone, other minor metabolites have been identified in rat liver microsomal incubation (Myung et al., 2000), rats feces, urine and plasma (Varkhede et al., 2014), human HepG2 cell lines (Zahno et al., 2011), human plasma (Ha et al., 2005), and human bile (Deng et al., 2011; Myung et al., 2000; Varkhede et al., 2014; Zahno et al., 2011). In the current study, we also observed several other amiodarone-derived metabolites, although the concentrations of these minor metabolites are much lower than desethylamiodarone (data not shown).
In vitro kinetics of amiodarone and its major metabolite in two human liver cell models after acute and repeated treatments
2015, Toxicology in VitroCitation Excerpt :The formation of MDEA in vivo is rapid and the disposition of both AMI and MDEA in humans is very similar. In human tissue, the MDEA concentration is even higher than that of AMI (Ha et al., 2005), in line with our results. This finding is particularly relevant since MDEA has been shown to be pharmacologically active (Deng et al., 2011) and recent in vitro investigations suggested that MDEA may be the cause for AMI’s hepatotoxicity (Zahno et al., 2011).
Amiodarone inhibits tissue factor expression in monocytic THP-1 cells
2013, European Journal of PharmacologyCitation Excerpt :Some studies have reported plasma concentrations of amiodarone and mono-N-desethylamiodarone (MDEA), which is the major metabolite of amiodarone, in patients having oral amiodarone daily. According to a report, plasma concentrations of amiodarone and MDEA in patients receiving 200 mg/day amiodarone orally for more than 2 months are 1163±435 and 970±347 μg/l, respectively (Ha et al., 2005). The highest concentration of amiodarone recorded in the study is 2366 μg/l. Another report shows plasma concentrations of amiodarone in patients having 200, 400, and 600 mg/day of amiodarone orally for at least one month are 1060±430, 1930±800, and 3460±1500 μg/l, respectively (Holt et al., 1983).
Clinical pharmacology of antiarrhythmic drugs
2012, Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease: Fourth Edition
- 1
Present address: Clariant Ltd., R&D Textile Dyes, Rothausstrasse 61, CH-4132 Muttenz 1, Switzerland.