title: Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate.
abstract: This study investigated the effects of pregnane X receptor (PXR/NR1I2) and CYP2B6 genetic variants on sodium ferulate (SF)-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered with and without SF pretreatment for 14 days in 33 healthy subjects. The area under the time-concentration curve (AUC) ratio of AUC_hyd (AUC(0-∞) of hydroxybupropion)/AUC_bup (AUC(0-∞) of bupropion) represents the CYP2B6 hydroxylation activity, which was significantly lower in CYP2B6*6 carriers (NR1I2 TGT noncarriers or carriers) than in noncarriers in both the basal and SF-induced states (p-value<0.05). AUC ratio and AUC_hyd of NR1I2 -24113AA variant were markedly lower than GA and GG genotypes (7.5±2.1 versus 14.5±3.3 and 20.6±1.1, and 8873±1431 versus 14,504±2218 and 17,586±1046) in the induced states. However, -24020(-)/(-) variant didn't show significant difference in the induction of CYP2B6 hydroxylation activity by SF compared with other -24020[GAGAAG]/(-) genotypes. NR1I2 TGT haplotype (-25385T+g.7635G+g.8055T) carriers exhibited a significantly decreased AUC ratio, compared with TGT noncarriers, in the basal states (7.6±1.0 versus 9.7±1.0), while this result wasn't observed in CYP2B6*6 noncarriers. Moreover, individuals with complete mutation-type [CYP2B6*6/*6+NR1I2 TGT+ -24113AA+ -24020 (-)/(-)] showed even lower percent difference of AUC ratio (8.7±1.2 versus 39.5±8.2) than those with complete wild-type. In conclusion, it is suggested that NR1I2 variants decrease the bupropion hydroxylation induced by SF treatment, particularly in CYP2B6*6 carriers.
  
  
  
  ChiCTR.org ChiCTR-TRC-11001285.
authors.affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Hunan Key laboratory of Pharmacogenetics, Central South University, Changsha, Hunan, China ; Department of Pharmacy, Changsha Central Hospital, Changsha, Hunan, China.
authors.forename: Lichen
authors.initials: L
authors.lastname: Gao
authors.forename: Yijing
authors.initials: Y
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Jiye
authors.initials: J
authors.lastname: Yin
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Huang
authors.forename: Fangqun
authors.initials: F
authors.lastname: Liu
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Ouyang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhaoqian
authors.initials: Z
authors.lastname: Liu
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000328:Adult; D016642:Bupropion / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D003373:Coumaric Acids / Q000494:pharmacology*; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D004347:Drug Interactions; D014644:Genetic Variation / Q000502:physiology; D005838:Genotype; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*; D055815:Young Adult
chemical_list: D003373:Coumaric Acids; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C580748:hydroxybupropion; D016642:Bupropion; C004999:ferulic acid; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6