The downfall of TBA-354 - a possible explanation for its neurotoxicity via mass spectrometric imaging.

Authors:
Dr Adeola Shobo, PhD
Dr Adeola Shobo, PhD
McGill University
Dr
Montreal , McGill University | Canada
Hendrik G Kruger
Hendrik G Kruger
University of KwaZulu-Natal
South Africa
Arndt Asperger
Arndt Asperger
Institute of Analytical Chemistry
Germany
Dagmar Niemeyer
Dagmar Niemeyer
Technische Universität München
Germany
Per I Arvidsson
Per I Arvidsson
Uppsala University
Sooraj Baijnath
Sooraj Baijnath
University of KwaZulu-Natal
South Africa

Xenobiotica 2018 Sep 13;48(9):938-944. Epub 2017 Oct 13.

a Catalysis and Peptide Research Unit, University of KwaZulu-Natal , Durban , South Africa.

1. TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. 2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20 mg/kg bw). 3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the C at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain. 4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds.

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http://dx.doi.org/10.1080/00498254.2017.1375168DOI Listing
September 2018
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