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Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate.

Gao L, He Y, Tang J, Yin J, Huang Z, Liu F, Ouyang D, Chen X, Zhang W, Liu Z, Zhou H - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

Trial registration: ChiCTR.org ChiCTR-TRC-11001285.

No MeSH data available.


Effects of NR1I2 TGT and CYP2B6*6 on induction of bupropion hydroxylation by SF.Individual profiles showing AUC_hyd/AUC_bup ratios for the basal and SF-induced states in the NR1I2 and CYP2B6 genotype groups (n = 33).
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pone-0062489-g001: Effects of NR1I2 TGT and CYP2B6*6 on induction of bupropion hydroxylation by SF.Individual profiles showing AUC_hyd/AUC_bup ratios for the basal and SF-induced states in the NR1I2 and CYP2B6 genotype groups (n = 33).

Mentions: As shown in Fig. 1, individual plots of CYP2B6 and NR1I2 variants indicated that the combination of NR1I2 TGT haplotype and CYP2B6*6 affected the AUC ratio in both the basal and induced states. The concentration-time profiles of hydroxybupropion were very different for CYP2B6*6+NR1I2 TGT carriers from other groups, with the lowest values in both the basal and induced states (see Fig. 2). The Cmax values of hydroxybupropion in the basal and induced states showed no significant difference between NR1I2 TGT carriers and noncarriers (unpublished data). However, the hydroxybupropion Cmax in CYP2B6*6+NR1I2 TGT carriers was significantly lower than CYP2B6*6+NR1I2 TGT noncarriers in both the basal and induced states (284.3±40.8 versus 395.2±40.5, and 332.9±27.6 versus 424.5±32.8, p-value<0.05).


Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate.

Gao L, He Y, Tang J, Yin J, Huang Z, Liu F, Ouyang D, Chen X, Zhang W, Liu Z, Zhou H - PLoS ONE (2013)

Effects of NR1I2 TGT and CYP2B6*6 on induction of bupropion hydroxylation by SF.Individual profiles showing AUC_hyd/AUC_bup ratios for the basal and SF-induced states in the NR1I2 and CYP2B6 genotype groups (n = 33).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3686783&req=5

pone-0062489-g001: Effects of NR1I2 TGT and CYP2B6*6 on induction of bupropion hydroxylation by SF.Individual profiles showing AUC_hyd/AUC_bup ratios for the basal and SF-induced states in the NR1I2 and CYP2B6 genotype groups (n = 33).
Mentions: As shown in Fig. 1, individual plots of CYP2B6 and NR1I2 variants indicated that the combination of NR1I2 TGT haplotype and CYP2B6*6 affected the AUC ratio in both the basal and induced states. The concentration-time profiles of hydroxybupropion were very different for CYP2B6*6+NR1I2 TGT carriers from other groups, with the lowest values in both the basal and induced states (see Fig. 2). The Cmax values of hydroxybupropion in the basal and induced states showed no significant difference between NR1I2 TGT carriers and noncarriers (unpublished data). However, the hydroxybupropion Cmax in CYP2B6*6+NR1I2 TGT carriers was significantly lower than CYP2B6*6+NR1I2 TGT noncarriers in both the basal and induced states (284.3±40.8 versus 395.2±40.5, and 332.9±27.6 versus 424.5±32.8, p-value<0.05).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

Trial registration: ChiCTR.org ChiCTR-TRC-11001285.

No MeSH data available.