rifampin and radafaxine

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.

Topics: Aryl Hydrocarbon Hydroxylases; Asian People; Bupropion; Cytochrome P-450 CYP2B6; Drug Interactions; Female; Genotype; Humans; Hydroxylation; Male; Oxidoreductases, N-Demethylating; Polymorphism, Single Nucleotide; Pregnane X Receptor; Receptors, Steroid; Rifampin

A sensitive and stereoselective assay has been developed for the quantitation of the enantiomers of hydroxybupropion, an active metabolite of bupropion, in human plasma. The assay used liquid-liquid extraction and a Cyclobond I 2000 HPLC column with a mobile phase containing 3% acetonitrile, 0.5% triethylamine, and 20 mM ammonium acetate (pH 3.8). The technique was linear over the concentration range of 12.5-500 ng/ml for (2R,3R)- and (2S,3S)-hydroxybupropion. The method was reproducible as both interday and intraday variabilities were less than 10% for both hydroxybupropion enantiomers. Overall extraction recovery of hydroxybupropion enantiomers and the internal standard phenacetin from plasma was greater than 80% and reproducible over the concentration range of 12.5-500 ng/ml for each enantiomer. The limit of quantification (LOQ) of hydroxybupropion enantiomers was 12.5 ng/ml. The stereoselective pharmacokinetics of both (2R,3R)- and (2S,3S)-hydroxybupropion in healthy male subjects (n = 16) were investigated after a single dose of (rac)-bupropion either alone or during rifampicin administration. (2R,3R)-Hydroxybupropion was the predominant enantiomer present in plasma. A stereoselective effect of rifampicin on hydroxybupropion concentrations was observed, with rifampicin influencing the pharmacokinetics of each hydroxybupropion enantiomer in a different manner. The ratio of (2R,3R)-hydroxybupropion (AUC(0-24)) to (2S,3S)-hydroxybupropion (AUC(0-24)) increased from 4.9 +/- 1.6 to 8.3 +/- 1.9 during rifampicin administration (P < 0.001). A time-dependent change in the hydroxybupropion enantiomeric ratio was observed after (rac)-bupropion administration both before and during rifampicin coadministration, with an increase in the relative proportion of (2S,3S)-hydroxybupropion over the 24 h postdose period.

Topics: Antibiotics, Antitubercular; Antidepressive Agents, Second-Generation; Bupropion; Chromatography, High Pressure Liquid; Humans; Male; Rifampin; Stereoisomerism