Unmasking efavirenz neurotoxicity: Time matters to the underlying mechanisms

Efavirenz is an anti-HIV drug that presents relevant short- and long-term central nervous system adverse reactions. Its main metabolite (8-hydroxy-efavirenz) was demonstrated to be a more potent neurotoxin than efavirenz itself. This work was aimed to understand how efavirenz biotransformation to 8-...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2017-07, Vol.105, p.47-54
Main Authors: Grilo, Nádia M., João Correia, M., Miranda, Joana P., Cipriano, Madalena, Serpa, Jacinta, Matilde Marques, M., Monteiro, Emília C., Antunes, Alexandra M.M., Diogo, Lucília N., Pereira, Sofia A.
Format: Article
Language:English
Subjects:
8-Hydroxy-efavirenz
Animals
Anti-HIV Agents - adverse effects
Anti-HIV Agents - blood
Anti-HIV Agents - pharmacokinetics
Aryl Hydrocarbon Hydroxylases - genetics
Aryl Hydrocarbon Hydroxylases - metabolism
Benzoxazines - adverse effects
Benzoxazines - blood
Benzoxazines - metabolism
Benzoxazines - pharmacokinetics
Biotransformation
CYP2B6
Cytochrome P-450 CYP2B1 - genetics
Cytochrome P-450 CYP2B1 - metabolism
Hippocampus - metabolism
Liver - metabolism
Male
Neurotoxicity Syndromes - blood
Neurotoxicity Syndromes - metabolism
Prefrontal Cortex - metabolism
Rats, Wistar
S-thiolated proteins
Steroid Hydroxylases - genetics
Steroid Hydroxylases - metabolism
Sulfhydryl Compounds - metabolism
Thiolomic signature
Time-dependent CYP450 induction
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Summary:Efavirenz is an anti-HIV drug that presents relevant short- and long-term central nervous system adverse reactions. Its main metabolite (8-hydroxy-efavirenz) was demonstrated to be a more potent neurotoxin than efavirenz itself. This work was aimed to understand how efavirenz biotransformation to 8-hydroxy-efavirenz is related to its short- and long-term neuro-adverse reactions. To access those mechanisms, the expression and activity of Cyp2b enzymes as well as the thiolomic signature (low molecular weight thiols plus S-thiolated proteins) were longitudinally evaluated in the hepatic and brain tissues of rats exposed to efavirenz during 10 and 36days. Efavirenz and 8-hydroxy-efavirenz plasma concentrations were monitored at the same time points. Cyp2b induction had a delayed onset in liver (p
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2017.05.010