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. 2016 Jul 22;60(8):4511-8.
doi: 10.1128/AAC.00280-16. Print 2016 Aug.

Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship With CYP2B6 c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis

Free PMC article

Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship With CYP2B6 c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis

Sam Nightingale et al. Antimicrob Agents Chemother. .
Free PMC article


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.


Relationship between concentrations of EFZ in plasma (a readily accessible and more easily measured parameter) and concentrations of EFZ and 8OH-EFZ in CSF. CSF and plasma EFZ concentrations were correlated in the TBM group (a) and the no-TBM group (b). No relationship was seen for 8OH-EFZ in either the TBM group (c) or the no-TBM group (d). NS, not significant.
Effect of CYP2B6 genotype on estimated effective and toxic concentrations of EFZ in plasma (a and b), EFZ in CSF (c and d), and total 8OH-EFZ in CSF (e and f). Error bars are geometric means and 95% confidence intervals for the GG/GT genotype and the geometric mean and range for the TT genotype. MTC, minimum toxic concentration; MEC, minimum effective concentration; ITC, in vitro toxic concentration.
Relationship between degree of blood-brain barrier breakdown, as measured by the CSF/blood albumin ratio, and the CSF concentrations of EFZ and 8OH-EFZ.

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