Mass Spectrometry Imaging Demonstrates the Regional Brain Distribution Patterns of Three First-Line Antiretroviral Drugs

Abstract

HIV in the central nervous system (CNS) contributes to the development of HIV-associated neurological disorders (HAND), even with chronic antiretroviral therapy. In order for antiretroviral therapy to be effective in protecting the CNS, these drugs should have the ability to localize in brain areas known to be affected by HIV. Consequently, this study aimed to investigate the localization patterns of three first-line antiretroviral drugs, namely, efavirenz, tenofovir, and emtricitabine, in the rat brain. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) were utilized to assess the pharmacokinetics and brain spatial distribution of the three drugs. Each drug was administered (50 mg/kg) to healthy female Sprague–Dawley rats via intraperitoneal administration. LC–MS/MS results showed that all three drugs could be delivered into the brain, although they varied in blood–brain barrier permeability. MALDI-MSI showed a high degree of efavirenz localization across the entire brain, while tenofovir localized mainly in the cortex. Emtricitabine distributed heterogeneously mainly in the thalamus, corpus callosum, and hypothalamus. This study showed that efavirenz, tenofovir, and emtricitabine might be a potential drug combination antiretroviral therapy for CNS protection against HAND.

The Lymph Node Reservoir: Physiology, HIV Infection, and Antiretroviral Therapy

“…94,95 Ntshangase et al performed qualitative MSI of tenofovir and elvitegravir in the brains of rats, and found preferential distribution of elvitegravir into the thalamus, hypothalamus, and corpus callosum; subsequent investigations by the same group also showed heterogeneity in emtricitabine and efavirenz distribution in rat brains, although neither of these studies quantified ARV concentrations in brain regions to determine the true extent of heterogeneity. 90,96 To fully understand how this ARV variability affects HIV persistence, it is crucial to investigate the overlap between ARVs and HIV expression in these sites. Furthermore, the location and concentration of drug proximate to virus must be determined to understand the potential true efficacy of ARVs within tissues.…”

“…Ntshangase et al . performed qualitative MSI of tenofovir and elvitegravir in the brains of rats, and found preferential distribution of elvitegravir into the thalamus, hypothalamus, and corpus callosum; subsequent investigations by the same group also showed heterogeneity in emtricitabine and efavirenz distribution in rat brains, although neither of these studies quantified ARV concentrations in brain regions to determine the true extent of heterogeneity 90,96 …”

A Meta-Analytic Review of the Effect of Antiretroviral Therapy on Neurocognitive Outcomes in Adults Living with HIV-1 in Low-and Middle-Income Countries

“…The domains of learning and memory, attention and working memory, language and motor function may be more refractory to improvement with ART. One of the hypotheses to explain the variability of ART's effect on cognitive domains is that the penetration pattern, localization, and distribution of ART within the brain regions differ (Ntshangase et al, 2019). This could be a plausible reason why the Central Penetrating Score (CPE) had no significant effect on cognitive performance.…”

“…The CPE scores are based on physicochemical, pharmacological, and clinical studies on ART and predict cognitive performance based on ART concentration in the CSF (Letendre et al, 2008). The CSF concentration may not be a reliable proxy for ART penetration in the CNS, hence a need for a more robust drug index that incorporates CSF concentration, viral reservoir eradication efficacy in the periphery and CNS, and spatial distribution in different brain regions (Novakovic et al, 2015;Ntshangase et al, 2019).…”

Removal of optimal cutting temperature (O.C.T.) compound from embedded tissue for MALDI imaging of lipids

“…Matrix-assisted laser desorption ionisation (MALDI) mass spectrometry imaging (MSI) is an invaluable method for direct tissue analysis that measures and visualises the relative abundance and spatial distribution of different biomolecules including peptides [1][2][3], drugs [4][5][6], lipids [7][8][9][10][11], nucleotides [12,13], and other cellular metabolites [14]. It is increasingly being adopted as an analytical technique by researchers characterising the fundamental molecular changes that occur in pathologies of disease, both infectious [15][16][17] and non-infectious [18].…”