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Toxicol Lett. 2016 Oct 17;260:28-35. doi: 10.1016/j.toxlet.2016.08.009. Epub 2016 Aug 16.

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

Author information

1
Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal.
2
Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal.
3
Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal; Centro Hospitalar de Lisboa Central, Lisboa, EPE, 1150-199, Lisboa, Portugal.
4
Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal. Electronic address: sofia.pereira@nms.unl.pt.

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.

KEYWORDS:

8-Hydroxy-efavirenz; 8-Hydroxy-efavirenz-glucuronide; Neurotoxicity; Pharmacokinetics

PMID:
27543169
DOI:
10.1016/j.toxlet.2016.08.009
[Indexed for MEDLINE]

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