Effects of pregnane X receptor (NR1I2) and CYP2B6 genetic polymorphisms on the induction of bupropion hydroxylation by rifampin.
We investigated genetic polymorphisms in the pregnane X receptor (NR1I2) in Korean individuals (n = 83) and the effects of NR1I2 genotypes on rifampin-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered before and after rifampin treatment for 7 days in 35 healthy subjects. The area under the time-concentration curve (AUC) ratio of hydroxybupropion to bupropion in CYP2B6*6 carriers was significantly lower than that in CYP2B6*6 noncarriers in both the basal and rifampin-induced states (p = 0.012). Among the CYP2B6*6 carriers (n = 13), the NR1I2 TGT (-25385T + g.7635G + g.8055T) carriers exhibited a significantly lower AUC ratio, representing the CYP2B6 hydroxylation activity, compared with the TGT noncarriers, in the induced state (11.9 versus 20.3, p = 0.045). The percent difference in the AUC ratio between the basal and induced states was also significantly different (212% versus 58.8%, p = 0.006). However, no significant difference was observed among the NR1I2 TGT genotypes for the CYP2B6*6 noncarriers (n = 22). In conclusion, it is suggested the NR1I2 TGT genotype decreases the bupropion hydroxylation induced by treatment with rifampin, particularly in CYP2B6*6 carriers.
Chung
Jae Yong
JY
Department of Pharmacology and Clinical Pharmacology, Yonsei University College of Medicine and Severance Hospital, Seoul, Korea.
Cho
Joo-Youn
JY
Lim
Hyeong-Seok
HS
Kim
Jung-Ryul
JR
Yu
Kyung-Sang
KS
Lim
Kyoung Soo
KS
Shin
Sang-Goo
SG
Jang
In-Jin
IJ
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D016642:Bupropion / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D065702:Cytochrome P-450 CYP2B6; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology*
C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C496215:radafaxine; D012293:Rifampin