Constitutive androstane receptor and pregnane X receptor genotype influence efavirenz plasma concentration and CYP2B6 enzyme activity

Efavirenz is metabolized by CYP2B6, an inducible enzyme whose expression is regulated by the constitutive androstane receptor and pregnane X receptor nuclear receptors. CAR and PXR are encoded by genetically polymorphic NR1I2 and NR1I3, respectively. We examined the impact of NR1I2 and NR1I3 genotype on plasma EFV concentration and CYP2B6 enzyme activity among TB-HIV co-infected patients in Ethiopia. Treatment-naive HIV patients with TB co-infection (n = 80) were enrolled and received first-line EFV-based antiretroviral and rifampicin-based anti-TB therapy. Plasma EFV and 8-hydroxy-EFV concentrations at the 4th and 16th week of EFV treatment were determined using LC/MS/MS. EFV/8-hydroxy-EFVmetabolic ratio was used as CYP2B6 metabolic activity index. In multivariate regression analysis, NR1I3 rs3003596C or NR1I2 rs2472677T variant allele carriers had significantly lower plasma EFV concentrations than non-carriers. Patients with NR1I2 rs3814057C/C genotype or NR1I3 rs3003596C allele carriers had significantly lower mean log EFV MR. Among CYP2B6*6 allele carriers, patients with NR1I3 rs2502815T/T or NR1I2 rs3814057C/C genotype had significantly lower mean log EFV MR. In conclusion, genetic variants in NR1I2 and NR1I3 genes influence plasma EFV exposure and CYP2B6 enzyme activity in TB-HIV co-infected patients on drug treatment.