title: Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship with CYP2B6 c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis.
abstract: Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published in vitro and in vivo data. The effect of the CYP2B6 c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the in vitro toxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the in vitro toxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the CYP2B6 genotype, particularly in those with impaired blood-brain barrier integrity.
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom s.nightingale@liv.ac.uk.
authors.forename: Sam
authors.initials: S
authors.lastname: Nightingale
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Tran Thi Hong
authors.initials: TT
authors.lastname: Chau
authors.affiliation: Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.affiliation: St. Stephen's AIDS Research Trust and Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Nelson
authors.affiliation: St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Carr
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Taylor
authors.affiliation: North Manchester General Hospital, Pennine Acute Hospitals NHS Trust, Manchester, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ustianowski
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Centre for Tropical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.affiliation: University of Cambridge, Department of Medicine, Cambridge, United Kingdom Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom Public Health England, Clinical Microbiology and Public Health Laboratory, Cambridge, United Kingdom.
authors.forename: M Estée
authors.initials: ME
authors.lastname: Törok
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D003521:Cyclopropanes; D005838:Genotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D014390:Tuberculosis, Meningeal / Q000188:drug therapy*
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz