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J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Oct 1;1096:154-159. doi: 10.1016/j.jchromb.2018.08.025. Epub 2018 Aug 25.

A rapid and sensitive liquid chromatography/tandem mass spectrometry assay for simultaneous quantitation of disopyramide and its major metabolite, mono-isopropyl-disopyramide, in rat plasma and its application to a pharmacokinetic study.

Author information

1
Department of Drug Metabolism and Pharmacokinetics, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea.
2
Drug Discovery Platform Technology Team, Medicinal Science Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea.
3
Department of Drug Metabolism and Pharmacokinetics, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea. Electronic address: ahnsh@kangwon.ac.kr.

Abstract

Disopyramide as an antiarrhythmic agent has been used for treating ventricular tachycardia and metabolized into its major metabolite, mono-isopropyl-disopyramide, by CYP3A4. We developed a novel, selective, highly sensitive, accurate, rapid method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of disopyramide and mono-isopropyl-disopyramide in rat plasma. This study is the first report for the assay validation using LC-MS/MS in biological fluids after simple protein-precipitation method. The most sensitive signals by multiple reaction monitoring (MRM) showed at m/z 340.2 → 239.2 and 298.2 → 239.2 with same fragment ion for disopyramide and mono-isopropyl-disopyramide, respectively. The lower limit of quantification (LLOQ) was determined at 2 ng/mL for both analytes and the linear concentration ranges were found to be 2-2000 ng/mL for disopyramide and 2-1000 ng/mL for mono-isopropyl-disopyramide. Finally, this assay was successfully applied to pharmacokinetic analysis of disopyramide and mono-isopropyl-disopyramide after oral and intravenous administration of disopyramide.

KEYWORDS:

Disopyramide; LC-MS/MS; Metabolite, pharmacokinetics; Mono-isopropyl-disopyramide

PMID:
30173081
DOI:
10.1016/j.jchromb.2018.08.025
[Indexed for MEDLINE]

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