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

Abstract

Fluoroquinolones are broad-spectrum antibiotics with efficacy against a wide range of pathogenic microbes associated with respiratory and meningeal infections. The potential toxicity of this class of chemical agents is a source of major concern and is becoming a global issue. The aim of this study was to develop a method for the brain distribution and the pharmacokinetic profile of gatifloxacin in healthy Sprague-Dawley rats, via Multicenter matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS). We developed a sensitive LC-MS/MS method to quantify gatifloxacin in plasma, lung, and brain homogenates. A pharmacokinetic profile was observed where there is a double peak pattern; a sharp initial increase in the concentration soon after dosing followed by a steady decline until another increase in concentration after a longer period post dosing in all three biological samples was observed. The imaging results showed the drug gradually entering the brain via the blood brain barrier and into the cortical regions from 15 to 240 min post dose. As time elapses, the drug leaves the brain following the same path as it followed on its entry and finally concentrates at the cortex. Copyright © 2015 John Wiley& Sons, Ltd.

Developing CHCA/PPD as a novel matrix for enhanced matrix‐assisted laser desorption/ionization‐mass spectrometry imaging for analysis of antibiotics in grass carp tissues

“…All quinolones appear in the form of [M + H] + in MS, and satisfactory intensity was observed at m/z 352.20, m/z 362.20, m/z 376.18, and m/z 334.19 for LOM, OFL, GAT, and PEF, respectively. And these peaks are basically consistent with the related detection research, 36–38 which proves that CHCA/PPD has the ability and suitability to detect quinolones and sulfonamides without disturbing the molecular structure.…”

“…The observed distribution characteristics are consistent with those reported in previous reports. 38,39 In addition to ENR in brain where the content is very low, the concentration levels in other tissues can be calculated using a linear regression curve (Figure S5…”

Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

“…Our simulations suggested that the optimal plasma AUC value in humans lies somewhere between 10 and 15 mg · h/liter, though the information required to extrapolate this to cerebral DAmB concentrations is not currently available. The application of noninvasive, high-resolution technologies, including matrix-assisted laser desorption ionization–mass spectroscopy imaging (MALDI-MSI), is now possible and offers the exciting potential to elucidate the pharmacokinetic/pharmacodynamic (PK/PD) index associated with efficacy at the site of infection by enabling quantification of drug in specific cerebral sites, as has been demonstrated in murine models that used gatifloxacin ( 37 ), doxycycline ( 38 ), pretomanid ( 39 ), and rifampin ( 40 ).…”

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

“…The precision (%RSD) and accuracy of the analyte in plasma and brain tissue was below 10%, all of which were within the limits set by the EMA (ESI Table 3 †). LC-MS/MS quantication has become the gold standard tool for assessing the concentration proles of a wide range of therapeutics in different biological matrices. 4,[6][7][8]22,[28][29][30][31][32][33] The optimized method was used to determine tissue pK, following a single dose of BDQ over a 24 h period. Quantitative data (LC-MS/MS) of BDQ in plasma and brain tissues following a single dose (25 mg kg À1 ) of i.p.…”

“…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.…”