Tissue distribution of an anti-TB drug, TBA-354 in rats via mass spectrometric investigations.

Abstract

Tuberculosis (TB) (TB) is one of the most well-recognized ancient human diseases in the history of mankind and it remains the major cause of human death amongst the transmittable diseases despite the use of antitubercular antibiotics. TB is caused by a pathogenic bacterium known as Mycobacterium tuberculosis (M.tb). The M.tb bacteria primary site of infection is the human lungs (resulting in pulmonary TB) but it can also affect other body parts (extrapulmonary TB) such as the bones, central nervous system (CNS), liver and many more others. Present-day TB research is focused on the development of more effective anti-TB drugs that can help shorten the treatment period. One of the major set-backs in TB drug development is to find the balance between the potential drug’s side effects and its activity. The present demonstrates the potential of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) techniques in the evaluation of the fundamental in-vivo pharmacokinetics and tissue distribution properties of a bicyclic nitroimidazole derivative, TBA-354. This drug is recognized to have an excellent activity against M.tb strains but also known to have mild signs of neurotoxicity. The use of MSI in this study shows the exact localization and accumulation of the drug in the brain, providing evidence as to why it showed certain neurotoxic signs during clinical trials. The study was conducted on healthy female Sprague-Dawley rats by administering 20 mg/kg of the drug, via an intraperitoneal (i.p.) route. After dosing the biological samples (plasma, lungs and brain) were collected at different time points for analysis. A validated LC-MS/MS method was used to quantify TBA-354 in rat plasma, lung and brain homogenate samples. LC-MS/MS cannot provide enough information regarding the drug localization and where it accumulates in the brain, therefore, MSI was then used to study the accumulation of the drug in different regions of the brain. As per LC-MS/MS results, the drug showed significant pharmacokinetic and distribution properties in the rat model with the highest levels in plasma compared to lung and brain. MALDI-MSI results showed that the drug was effectively able cross the blood-brain barrier (BBB) resulting in toxic accumulation in the neocortical regions of the brain. This study has proven the efficacy of MSI as a suitable analytical technique that can be used in future preclinical studies to evaluate the neurotoxicity of drugs targeting the brain, thus minimizing possible side effects.