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

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 a...

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Autores principales: Gao, Lichen, He, Yijing, Tang, Jie, Yin, Jiye, Huang, Zhengyu, Liu, Fangqun, Ouyang, Dongsheng, Chen, Xiaoping, Zhang, Wei, Liu, Zhaoqian, Zhou, Honghao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686783/
https://www.ncbi.nlm.nih.gov/pubmed/23840296
http://dx.doi.org/10.1371/journal.pone.0062489
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author Gao, Lichen
He, Yijing
Tang, Jie
Yin, Jiye
Huang, Zhengyu
Liu, Fangqun
Ouyang, Dongsheng
Chen, Xiaoping
Zhang, Wei
Liu, Zhaoqian
Zhou, Honghao
author_facet Gao, Lichen
He, Yijing
Tang, Jie
Yin, Jiye
Huang, Zhengyu
Liu, Fangqun
Ouyang, Dongsheng
Chen, Xiaoping
Zhang, Wei
Liu, Zhaoqian
Zhou, Honghao
author_sort Gao, Lichen
collection PubMed
description 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
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spelling pubmed-36867832013-07-09 Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate Gao, Lichen He, Yijing Tang, Jie Yin, Jiye Huang, Zhengyu Liu, Fangqun Ouyang, Dongsheng Chen, Xiaoping Zhang, Wei Liu, Zhaoqian Zhou, Honghao PLoS One Research Article 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 Public Library of Science 2013-06-19 /pmc/articles/PMC3686783/ /pubmed/23840296 http://dx.doi.org/10.1371/journal.pone.0062489 Text en © 2013 Gao et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gao, Lichen
He, Yijing
Tang, Jie
Yin, Jiye
Huang, Zhengyu
Liu, Fangqun
Ouyang, Dongsheng
Chen, Xiaoping
Zhang, Wei
Liu, Zhaoqian
Zhou, Honghao
Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate
title Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate
title_full Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate
title_fullStr Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate
title_full_unstemmed Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate
title_short Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate
title_sort genetic variants of pregnane x receptor (pxr) and cyp2b6 affect the induction of bupropion hydroxylation by sodium ferulate
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686783/
https://www.ncbi.nlm.nih.gov/pubmed/23840296
http://dx.doi.org/10.1371/journal.pone.0062489
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