Simultaneous determination of a novel oxazolidinone anti-tuberculosis OTB-658 and its metabolites in monkey blood by LC-MS/MS.

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Simultaneous determination of a novel oxazolidinone anti-tuberculosis OTB-658 and its metabolites in monkey blood by LC-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jan 18;1167:122552

Authors: Jiang J, Liu Y, Liu X, Zhang D, Huang H, Wang B, Sheng L, Li Y

Abstract
OTB-658, a novel oxazolidinone anti-tuberculosis agent, has potent antibacterial activity against Mycobacterium tuberculosis, especially multi-drug resistant tuberculosis (MDR-TB) in vitro and in vivo. In this study, after metabolite identification of parent drug OTB-658, a specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated to quantify OTB-658 and its metabolites OTB-665 and OTB-698 in monkey blood. HHY-1442, an analogue compound of OTB-658, was used as the internal standard. Blood samples were prepared by direct protein precipitation. Separation was performed on a Zorbax SB C18 column (50 mm × 2.1 mm, 3.5 μm) with a gradient mobile phase of methanol/water at a flow rate of 0.3 mL/min. The detection was conducted by a positive electrospray ionization in multiple-reaction monitoring mode on a triple quadrupole MS. The monitored transitions were m/z 382.2 → 221.1 for OTB-658, m/z 398.2 → 308.1 for OTB-665, m/z 414.1 → 372.3 for OTB-698 and m/z 418.2 → 311.3 for HHY-1442, respectively. Good linearity was observed over the range of 10-2000 ng/mL for OTB-658 and OTB-665, and 5-1000 ng/mL for OTB-698. All the intra-day and inter-day precision for the three analytes was below 8.4%, and the accuracy ranged from 96.0% to 106.0%. All analytes were stable during storage, preparation, and analytical procedures. The validated method was successfully applied to pharmacokinetic and bioavailability studies of OTB-658 in cynomolgus monkeys and the absolute bioavailability of OTB-658 was 25.0% at an oral dose of 10 mg/kg.

PMID: 33588346 [PubMed - as supplied by publisher]