Spatial Distribution Profiles of Emtricitabine, Tenofovir, Efavirenz, and Rilpivirine in Murine Tissues Following In Vivo Dosing Correlate with Their Safety Profiles in Humans

Abstract

Emtricitabine (FTC), tenofovir (TFV), efavirenz (EFV), and rilpivirine (RPV) are currently used as components of HIV combination therapy. Although these drugs are widely used in antiretroviral therapy, several organ toxicities related to TFV and EFV have been observed clinically. TFV is associated with nephrotoxicity, whereas EFV-related hepatotoxicity and neurotoxicity have been reported. While the precise molecular mechanisms related to the above-mentioned clinically observed toxicities have yet to be elucidated, understanding the local tissue distribution profiles of these drugs could yield insights into their safety profiles. To date, the distributions of these drugs in tissue following in vivo exposure are poorly understood. Therefore, in this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging method to generate spatial distribution profiles of FTC, TFV, EFV, and RPV in mouse tissues following in vivo dosing of following drug regimens: TFV–FTC–EFV and TFV–FTC–RPV. For this study, liver, brain, kidney, spleen, and heart tissues were obtained from mice ( n = 3) following separate oral administration of the above-mentioned drug regimens. Interestingly, EFV was detected in liver, brain, and heart following TFV–FTC–EFV treatment. Additionally, hydroxylated EFV, which encompasses the cytochrome P450-dependent monooxygenated metabolites of EFV, was detected in liver, brain, spleen, and heart tissue sections. Notably, the tissue distribution profiles of RPV and hydroxylated RPV following in vivo dosing of TFV–FTC–RPV were different from EFV/hydroxylated EFV despite RPV belonging to the same drug class as EFV. In conclusion, the observed spatial distribution profiles of the study drugs are in agreement with their safety profiles in humans.

Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis

“…Orthogonal technologies such as LC–MS/MS and MALDI-IMS are helpful in characterizing the samples in terms of accurate, sensitive, integrated drug concentrations for PK-PD analyses (LC–MS/MS) and as spatial analyte distribution to understand more nuanced drug localization (MALDI-IMS). To complement traditional LC–MS/MS approaches, imaging mass spectrometry has been applied to visualize ARV drug distribution in a variety of sample types following bolus dosing 70 – 74 . These studies elegantly showed the usefulness of MALDI-IMS in the context of HIV/AIDS prevention and treatment research.…”

Achieving a Deeper Understanding of Drug Metabolism and Responses Using Single-Cell Technologies

“…A tissue section is coated with a matrix and a laser is used to ablate ions from small regions for detection by mass spectrometry Imaging of endogenous metabolites as well as parent drugs and drug metabolites within tissues (Seneviratne et al, 2020) Label-free, direct detection of molecules…”

“…The main ionization techniques used for MSI are matrix-assisted laser desorption/ionization (MALDI), desorption electrospray ionization, laser ablation electrospray ionization, and secondary ion mass spectrometry (SIMS) ( Buchberger et al, 2018 ). Of these ionization techniques, MALDI MSI is the most frequently employed for simultaneous visualization of the spatial distribution of drugs, their metabolites, and endogenous lipid molecules at tissue level ( Prideaux et al, 2010 ; Seneviratne et al, 2018 ; Tang et al, 2019 ; Seneviratne et al, 2020 ). Due to recent improvements in MALDI MS sources, this approach can also be used for single cell imaging.…”

Humanized Mice for Infectious and Neurodegenerative disorders

“…This new model to study HIV brain infection also aid in the development and testing of new generation ART delivery with improved CNS bioavailability and will be useful for future viral eradication studies. Further, the model now allows studies of newly emerging ART-induced neurotoxicity such as reported for efavirenz [107,108]. However, many laboratory and animal studies have shown a number of direct effects on neuronal and glial function along with pathological outcomes that are linked to amyloid deposition, small vessel damage and aberrations in chemical neurotransmission [109][110][111][112][113][114].…”