title: Efavirenz biotransformation as an up-stream event of mood changes in HIV-infected patients.
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.
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal.
authors.forename: Nádia M
authors.initials: NM
authors.lastname: Grilo
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal.
authors.forename: M João
authors.initials: MJ
authors.lastname: Correia
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Sequeira
authors.affiliation: Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal.
authors.forename: Shrika G
authors.initials: SG
authors.lastname: Harjivan
authors.affiliation: 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.
authors.forename: Umbelina
authors.initials: U
authors.lastname: Caixas
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal.
authors.forename: Lucília N
authors.initials: LN
authors.lastname: Diogo
authors.affiliation: Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal.
authors.forename: M Matilde
authors.initials: MM
authors.lastname: Marques
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-052, Lisboa, Portugal.
authors.forename: Emília C
authors.initials: EC
authors.lastname: Monteiro
authors.affiliation: Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal.
authors.forename: Alexandra M M
authors.initials: AM
authors.lastname: Antunes
authors.affiliation: 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.
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Pereira
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001007:Anxiety / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology; D048588:Benzoxazines / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000097:blood; D001711:Biotransformation; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D003521:Cyclopropanes; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005240:Feasibility Studies; D020719:Glucuronides / Q000097:blood / Q000378:metabolism; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D006801:Humans; D008297:Male; D050217:Metabolic Detoxication, Phase II; D008875:Middle Aged; D019964:Mood Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D015995:Prevalence; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D054316:Biomarkers, Pharmacological; D003521:Cyclopropanes; D020719:Glucuronides; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz; C570209:8-hydroxyefavirenz
keywords: 8-Hydroxy-efavirenz; 8-Hydroxy-efavirenz-glucuronide; Neurotoxicity; Pharmacokinetics