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Optimized LC-MS/MS quantification of tuberculosis drug candidate macozinone (PBTZ169), its dearomatized Meisenheimer Complex and other metabolites, in human plasma and urine.
- Source :
-
Journal of Chromatography B: Analytical Technologies in the Biomedical & Life Sciences . Jan2023, Vol. 1215, pN.PAG-N.PAG. 1p. - Publication Year :
- 2023
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Abstract
- • LC-MS/MS methods for macozinone, a drug against multi-drug-resistant tuberculosis, and metabolites in plasma and urine. • Allows the quantification of the reduced metabolite H 2 PBTZ obtained by dearomatization of macozinone. • H 2 PBTZ among the first examples of Meisenheimer Complex (MC) metabolites identified in mammals. • Comprehensive stability studies of H 2 PBTZ in plasma and urine. • Application to analyses of samples collected during Phase Ib clinical trials with healthy subjects. Tuberculosis, and especially multidrug-resistant tuberculosis (MDR-TB), is a major global health threat which emphasizes the need to develop new agents to improve and shorten treatment of this difficult-to-manage infectious disease. Among the new agents, macozinone (PBTZ169) is one of the most promising candidates, showing extraordinary potency in vitro and in murine models against drug-susceptible and drug-resistant Mycobacterium tuberculosis. A previous analytical method using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed by our group to support phase I clinical trials of PBTZ169. These plasma sample analyses revealed the presence of several additional metabolites among which the most prominent was H 2 PBTZ, a reduced species obtained by dearomatization of macozinone, one of the first examples of Meisenheimer Complex (MC) metabolites identified in mammals. Identification of these new metabolites required the optimization of our original method for enhancing the selectivity between isobaric metabolites as well as for ensuring optimal stability for H 2 PBTZ analyses. Sample preparation methods were also developed for plasma and urine, followed by extensive quantitative validation in accordance with international bioanalytical method recommendations, which include selectivity, linearity, qualitative and quantitative matrix effect, trueness, precision and the establishment of accuracy profiles using β-expectation tolerance intervals for known and newer analytes. The newly optimized methods have been applied in a subsequent Phase Ib clinical trial conducted in our University Hospital with healthy subjects. H 2 PBTZ was found to be the most abundant species circulating in plasma, underscoring the importance of measuring accurately and precisely this unprecedented metabolite. Low concentrations were found in urine for all monitored analytes, suggesting extensive metabolism before renal excretion. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15700232
- Volume :
- 1215
- Database :
- Academic Search Index
- Journal :
- Journal of Chromatography B: Analytical Technologies in the Biomedical & Life Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 161345121
- Full Text :
- https://doi.org/10.1016/j.jchromb.2022.123555