Optimized LC-MS/MS quantification of tuberculosis drug candidate macozinone (PBTZ169), its dearomatized Meisenheimer Complex and other metabolites, in human plasma and urine
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Le résumé fourni par la source
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 H2PBTZ, 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 H2PBTZ 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. H2PBTZ 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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Optimized LC-MS/MS quantification of tuberculosis drug candidate macozinone (PBTZ169), its dearomatized Meisenheimer Complex and other metabolites, in human plasma and urine
- Date Crossref
- 01/01/2023
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Centre Hospitalier Universitaire Vaudois pays non établi dans la noticeÉtablissement de santé
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University of Lausanne Laboratory & Service of Clinical Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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École Polytechnique Fédérale de Lausanne pays non établi dans la noticeUniversité ou école supérieure
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Innovative Medicines for Tuberculosis Foundation pays non établi dans la noticeInstitution
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Federal Research Centre «Fundamentals of Biotechnology» of the Russian Academy of Sciences pays non établi dans la noticeStructure de recherche
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Hôpital Orthopédique de la Suisse Romande pays non établi dans la noticeÉtablissement de santé
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School of Life Sciences Global Health Institute pays non établi dans la noticeUniversité ou école supérieure
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Innovative Medicines for Tuberculosis (IM4TB) pays non établi dans la noticeInstitution
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Federal Research Center "Fundamentals of Biotechnology RAS" Switzerland pays non établi dans la noticeStructure de recherche
Centre Hospitalier Universitaire Vaudois, Laboratory & Service of Clinical Pharmacology — University of Lausanne et École Polytechnique Fédérale de Lausanne, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.