Visualization of Time-Dependent Distribution of Rifampicin in Rat Brain Using MALDI MSI and Quantitative LCMS/MS

Abstract

Rifampicin (RIF) is a major component for short-course chemotherapy against tuberculosis, since it is active against rapidly metabolizing as well as dormant bacteria. According to the Lipinski rules, RIF should not enter the blood-brain barrier. Visualization of tissue drug distribution is of major importance in pharmacological studies; thus, far imaging of RIF in the brain has been limited to positron emission tomography. We propose using matrix-assisted laser desorption/ionization mass spectrometry imaging techniques as a suitable alternative for the visualization and localization of drug tissue distribution. Using the liquid chromatography mass spectrometric (LCMS) technique, we were able to quantify the concentrations of RIF in the uninfected rat brain; we paired this with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to show the time-dependent manner in which RIF is able to enter the brain. Our results show that even at the minute concentrations measured with LCMS/MS we were able visualize the drug and show its exact distribution in the rat brain. Other available methods require nuclear labeling and the detection of gamma rays produced by labeled compounds to visualize the compound and its localization; MALDI MSI is a more recently developed technique, which can provide detailed information on drug distribution in tissues when compared to other imaging techniques. This study shows that without any requirement for complex preprocessing we are able to produce images with a relatively improved resolution and localization than those acquired using more complex imaging methods, showing MALDI MSI to be an invaluable tool in drug distribution studies.

MALDI MSI and LC‐MS/MS: Towards preclinical determination of the neurotoxic potential of fluoroquinolones

“…Matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) is a label‐free technique, which offers the advantage of determining the distribution of parent drug and metabolites simultaneously . We have recently shown that a combination of liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) with MALDI MSI provides better correlation than PET imaging technique . The aim of this study was to establish methods for the preclinical evaluation and localization of fluoroquinolones in the rat brain by using LC‐MS/MS and MALDI MSI as sensitive tools for its determination.…”

Tissue distribution of pretomanid in rat brain via mass spectrometry imaging

“…Using this information, we propose that pretomanid is able to diffuse into the neighbouring lateral ventricles and follows the rostral migratory stream to the olfactory area leading to the observed reduction in drug distribution after 120 min in the CC. The findings we have presented in this article together with previous reports indicate that the distribution and localisation of drugs in the brain vary among different groups of antibiotics depending on their structural and chemical properties (Liu et al, 2010;Mindermann et al, 1993;Shobo et al, 2015).…”

Bedaquiline has potential for targeting tuberculosis reservoirs in the central nervous system

“…1 In the most recent TB drug pipeline, there are several novel agents, many of which are currently undergoing clinical trials to determine their potential against TB. [2][3][4][5][6][7][8] Amongst them, BDQ has proven to be a promising rst-in-class US FDA approved anti-TB agent, which belongs to the diarylquinoline class of antibiotics. BDQ is proposed for the treatment of multidrugresistant tuberculosis (MDR-TB) in combination with other active anti-TB drugs, when an effective therapy regimen could not be established.…”

“…Recently, our research group studied the localization and bio-distribution of TB drugs (clofazimine, linezolid, rifampicin, pretomanid, TBA-354) in the rodent brain. [2][3][4]6,7,22 However, these drugs offer partial protection in the CNS, thus further improvements in TB chemotherapy is required. 3,4 At present, limited data is available on the localization and distribution of BDQ in the brain.…”