Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites.
J Antimicrob Chemother
; 74(3): 699-709, 2019 03 01.
Article
em En
| MEDLINE
| ID: mdl-30535366
ABSTRACT
BACKGROUND:
There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz.OBJECTIVES:
We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance.METHODS:
We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold.RESULTS:
We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (ß = 0.38, P = 2.7â×â10-03), plasma 7-hydroxy-efavirenz (ß = 0.59, P = 3.7â×â10-03), plasma 8-hydroxy-efavirenzefavirenz ratio (ß = -0.31, P = 1.8â×â10-04) and CSF efavirenz (ß = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (ß = -0.55, P = 3.5â×â10-05), ABCB1 rs115780656 (ß = -0.65, P = 4.1â×â10-05) and CYP2A6 -48AâC (ß = -0.59, P = 0.01). CYP2A6 -48AâC was independently associated with higher CSF 8-hydroxy-efavirenzefavirenz ratio (ß = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenzefavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSFplasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance.CONCLUSIONS:
We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenzefavirenz ratio, plasma 8-hydroxy-efavirenzefavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenzefavirenz ratio.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Farmacogenética
/
Sistema Nervoso Central
/
Inibidores da Transcriptase Reversa
/
Benzoxazinas
/
Variantes Farmacogenômicos
Limite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article