TY - JOUR
T1 - Spatial Distribution Profiles of Emtricitabine, Tenofovir, Efavirenz, and Rilpivirine in Murine Tissues following in Vivo Dosing Correlate with Their Safety Profiles in Humans
AU - Seneviratne, Herana Kamal
AU - Hamlin, Allyson N.
AU - Heck, Carley J.S.
AU - Bumpus, Namandjé N.
N1 - Funding Information:
This research was funded by the National Institutes of Health [Grants U19AI11327, UM1 AI068613, and R01AI128781].
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/8/14
Y1 - 2020/8/14
N2 - 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.
AB - 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.
KW - antiretrovirals
KW - efavirenz
KW - emtricitabine
KW - mass spectrometry imaging
KW - rilpivirine
KW - tenofovir
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U2 - 10.1021/acsptsci.0c00015
DO - 10.1021/acsptsci.0c00015
M3 - Article
C2 - 32832868
AN - SCOPUS:85090593780
SN - 2575-9108
VL - 3
SP - 655
EP - 665
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 4
ER -