Development and validation of a highly sensitive LC-ESI-MS/MS method for estimation of IIIM-MCD-211, a novel nitrofuranyl methyl piperazine derivative with potential activity against tuberculosis: Application to drug development.

Abstract

In the present study, a simple, sensitive, specific and rapid liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was developed and validated according to the Food and Drug Administration (FDA) guidelines for estimation of IIIM-MCD-211 (a potent oral candidate with promising action against tuberculosis) in mice plasma using carbamazepine as internal standard (IS). Bioanalytical method consisted of one step protein precipitation for sample preparation followed by quantitation in LC-MS/MS using positive electrospray ionization technique (ESI) operating in multiple reaction monitoring (MRM) mode. Elution was achieved in gradient mode on High Resolution Chromolith RP-18e column with mobile phase comprised of acetonitrile and 0.1% (v/v) formic acid in water at the flow rate of 0.4mL/min. Precursor to product ion transitions (m/z 344.5/218.4 and m/z 237.3/194.2) were used to measure analyte and IS, respectively. All validation parameters were well within the limit of acceptance criteria. The method was successfully applied to assess the pharmacokinetics of the candidate in mice following oral (10mg/kg) and intravenous (IV; 2.5mg/kg) administration. It was also effectively used to quantitate metabolic stability of the compound in mouse liver microsomes (MLM) and human liver microsomes (HLM) followed by its in-vitro-in-vivo extrapolation.

• Authors: Asmita Magotra, Anjna Sharma, Ajai Prakash Gupta, Priya Wazir, Shweta Sharma, Parvinder Pal Singh, Manoj Kumar Tikoo, Ram A Vishwakarma, Gurdarshan Singh, Utpal Nandi
• Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences (J Chromatogr B Analyt Technol Biomed Life Sci) Vol. 1060 Pg. 200-206 (Aug 15 2017) ISSN: 1873-376X [Electronic] Netherlands
• PMID: 28623772 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Antitubercular Agents
• Nitrofurans
• Piperazines

Topics

• Animals
• Antitubercular Agents (analysis, chemistry, pharmacokinetics, pharmacology)
• Chromatography, Liquid (methods)
• Limit of Detection
• Linear Models
• Male
• Mice
• Microsomes, Liver (metabolism)
• Mycobacterium tuberculosis (drug effects)
• Nitrofurans (analysis, chemistry, pharmacokinetics, pharmacology)
• Piperazines (analysis, chemistry, pharmacokinetics, pharmacology)
• Reproducibility of Results
• Spectrometry, Mass, Electrospray Ionization (methods)
• Tandem Mass Spectrometry (methods)
• Tuberculosis