83409-32-9Relevant articles and documents
Rapid liquid chromatographic assay for the determination of amiodarone and its N-deethyl metabolite in plasma, urine, and bile
Weir,Ueda
, p. 460 - 465 (1985)
A rapid high-performance liquid chromatographic assay was developed for the determination of amiodarone (1) and its N-deethyl metabolite (desethylamiodarone, 2) in plasma, urine, and bile. Analysis was performed on a C18 reversed-phase column and precolumn using a mobile phase consisting of methanol:water:58% ammonium hydroxide (94:4:2) delivered at a flow rate of 1.5 mL/min. The eluant was monitored at 244 nm. Under these conditions, 1, 2, and the internal standard eluted with retention times of 5.5, 4.6, and 6.8 min, respectively. Samples (100 μL) of plasma were prepared by precipitating the plasma proteins with acetonitrile containing the internal standard and injecting an aliquot of the supernatant directly onto the column. Samples (100 μL) of urine and bile were prepared for injection by acidifying the sample with concentrated HCl and then extracting the mixture with six volumes of 2,2-dimethoxyproprane. The recovery of 1 and 2 from plasma was virtually complete. The recovery from urine and bile was 80-90% for 1 and 60-65% for 2. The limit of sensitivity of both compounds in plasma was 100 ng/mL. For urine and bile, the detection limits were 1 and 5 μg/mL, respectively. Over the plasma concentration range of 0.1-10.0 μg/mL, the within-day CV ranged from 1 to 10% for 1 and from 1 to 8% for 2. The between-day CV ranged from 2 to 12% and from 1 to 17% for 1 and 2, respectively. Of 44 drugs tested for potential assay interference, four interfered with the determination of 2 and one with the analysis of 1. The assay has been used for pharmacokinetic studies in rats and routine monitoring of concentrations of 1 and 2 in human plasma.
Quantification of electrochemically generated iodine-containing metabolites using inductively coupled plasma mass spectrometry
Lohmann, Wiebke,Meermann, Bjoern,Moeller, Ines,Scheffer, Andy,Karst, Uwe
, p. 9769 - 9775 (2008)
For the risk assessment of drug candidates, the identification and quantification of their metabolites is required. The majority of analytical techniques is based on calibration standards for quantification of the metabolites. As these often are not readily available, the use of inductively coupled plasma mass spectrometry (ICPMS) is an attractive alternative for drugs containing heteroatoms. In this work, the online coupling of electrochemistry (EC), liquid chromatography (LC), and ICPMS is presented. The antiarrhythmic agent amiodarone, which contains two iodine atoms, is oxidized in an electrochemical flow-through cell under N-dealkylation and deiodination. The metabolites that are generated at different EC potentials are identified by electrospray ionization (ESI) mass spectrometry, compared to those from rat liver microsomal incubations and quantified by ICPMS. Phase-optimized LC, a recent approach for high-performance isocratic separations, is used to avoid the ICPMS calibration problems known to occur with gradient separations. The potential of the complementary use of ESI-MS and ICPMS for the qualitative and quantitative analysis of drug metabolites becomes apparent in this work.
Preparation and purification of desethylamiodarone hydrochloride
Lucas, Anthony N.,Tanol, Mehmet,McIntosh, Michelle P.,Rajewski, Roger A.
, p. 3371 - 3376 (2006)
Reaction of the free base of amiodarone with 1-chloroethyl chloroformate in toluene gives desethylamiodarone, which can be easily purified and converted to the hydrochloride salt. Copyright Taylor & Francis Group, LLC.
Comparative analysis of in vivo and in silico toxicity evaluation of the organoiodine compounds towards D. magna using multivariate chemometric approach: A study on the example of amiodarone phototransformation products
Skibiński, Robert,Trawiński, Jakub
, (2022/01/06)
In the present study the photochemical fate of organoiodine compound – amiodarone was performed. The drug turned out to be highly susceptible to UV–Vis irradiation, especially in the presence of humic substances and organic matrix. Qualitative LC-MS analysis revealed formation of twelve – mainly previously unreported – transformation products (TPs). Four major TPs were submitted to the toxicity analysis with the use of D. magna. All of the tested TPs presented higher toxic potential than the parent compound. The phenolic TPs were approximately 100 times more toxic than amiodarone. Toxic properties of the major TPs resulted in steadily increasing toxic potential of the photo-generated mixture over the time of irradiation. Moreover, the experimental toxicity data, concerning the TPs, were compared with results estimated by 6 in silico models with the use of a multivariate chemometric analysis. The results showed that the applied computational methods were able neither to correctly predict toxic properties of the studied compounds, nor the trends in change of their toxic parameters. Additional validation of in silico models ability to predict toxicity of iodinated organic compounds showed that the studied computational methods do not present sufficient prediction ability. Therefore their estimations concerning organoiodines should be verified using experimental tests.
Identification of novel substrates for human cytochrome P450 2J2
Lee, Caroline A.,Neul, David,Clouser-Roche, Andrea,Dalvie, Deepak,Wester, Michael R.,Jiang, Ying,Jones III,Freiwald, Sascha,Zientek, Michael,Totah, Rheem A.
scheme or table, p. 347 - 356 (2010/11/18)
Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential CYP2J2 substrates. Eight novel substrates were identified that vary in size and overall topology from relatively rigid structures (amiodarone) to larger complex structures (cyclosporine). The substrates displayed in vitro intrinsic clearance values ranging from 0.06 to 3.98 μl/min/pmol CYP2J2. Substrates identified for CYP2J2 are also metabolized by CYP3A4. Extracted ion chromatograms of metabolites observed for albendazole, amiodarone, astemizole, thioridazine, mesoridazine, and danazol showed marked differences in the regioselectivity of CYP2J2 and CYP3A4. CYP3A4 commonly metabolized compounds at multiple sites, whereas CYP2J2 metabolism was more restrictive and limited, in general, to a single site for large compounds. Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. For albendazole, CYP2J2 forms a unique metabolite compared with CYP3A4. Albendazole and amiodarone were evaluated in various in vitro systems including recombinant CYP2J2 and CYP3A4, pooled human liver microsomes (HLM), and human intestinal microsomes (HIM). The Michaelis-Menten-derived intrinsic clearance of N-desethyl amiodarone was 4.6 greater in HLM than in HIM and 17-fold greater in recombinant CYP3A4 than in recombinant CYP2J2. The resulting data suggest that CYP2J2 may be an unrecognized participant in first-pass metabolism, but its contribution is minor relative to that of CYP3A4. Copyright
