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Efavirenz biotransformation as an up-stream event of mood changes in HIV-infected patients.

Efavirenz biotransformation as an up-stream event of mood changes in HIV-infected patients.
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Grilo NM, Correia MJ, Sequeira C, Harjivan SG, Caixas U, Diogo LN, Marques MM, Monteiro EC, Antunes AM, Pereira SA,


Grilo NM, Correia MJ, Sequeira C, Harjivan SG, Caixas U, Diogo LN, Marques MM, Monteiro EC, Antunes AM, Pereira SA, (click to view)

Grilo NM, Correia MJ, Sequeira C, Harjivan SG, Caixas U, Diogo LN, Marques MM, Monteiro EC, Antunes AM, Pereira SA,

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Toxicology letters 2016 Aug 16260() 28-35 pii 10.1016/j.toxlet.2016.08.009

Abstract

Efavirenz is a drug of choice for adults and children infected with the human immunodeficiency virus. Notably, up to 35% of patients on efavirenz suffer from mood changes. This work aimed to investigate efavirenz biotransformation into 8-hydroxy-efavirenz as an up-stream event of mood changes and to evaluate the suitability of 8-hydroxy-efavirenz biomonitoring for the minimization of these manifestations. A case-control study with two age-matched groups of HIV-infected male patients was performed in a group without adverse central nervous system complaints (28 patients) and a group presenting mood changes (14 patients). The plasma concentration of non-conjugated 8-hydroxy-efavirenz was higher in patients with mood changes (p=0.020). An association between efavirenz and 8-hydroxy-efavirenz-glucuronide was found (Spearman r=0.414, p<0.010), only within therapeutic efavirenz concentrations. This correlation was not observed in patients with toxic (>4mg/L) plasma concentrations of the parent drug. We conclude that metabolism to 8-hydroxy-efavirenz is associated with efavirenz-related mood changes, which suggests that the concentration of this metabolite is a suitable parameter for therapeutic drug monitoring aimed at controlling these manifestations. Moreover, our data suggest that 8-hydroxy-efavirenz is able to cross the blood-brain barrier and that the peripheral detoxification of 8-hydroxy-efavirenz by glucuronidation may be inhibited by toxic efavirenz concentrations.

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