Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity.
OBJECTIVE
The aim of this study was to investigate the activity of the drug-metabolizing enzyme cytochrome P450 (CYP) 2B6 before and after in vivo induction by rifampin (INN, rifampicin) in white subjects and Chinese subjects by use of the probe drug bupropion (INN, amfebutamone).


METHODS
Healthy male white subjects (n = 9) and Chinese subjects (n = 9) (age range, 19-34 years) of known CYP2B6 genotype received orally administered bupropion (Zyban SR, 150 mg) alone and during daily treatment with rifampin (600 mg). Blood samples were taken for up to 72 hours after each bupropion dose, and plasma concentrations of bupropion and its active metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, were measured by HPLC. The subjects' CYP2B6 genotype was determined by use of a matrix-assisted laser desorption /ionization-time of flight (MALDI-TOF) mass spectrometry assay.


RESULTS
Rifampin treatment increased the apparent clearance of bupropion in Chinese subjects and white subjects combined (n = 16) from 2.6 L x h(-1) x kg(-1) (95% confidence interval [CI], 2.3-3.0 L x h(-1) x kg(-1)) after bupropion alone to 7.9 L x h(-1) x kg(-1) (95% CI, 6.8-10.1 L x h(-1) x kg(-1)) during rifampin treatment. Rifampin treatment decreased the half-life of bupropion from 15.9 hours (95% CI, 13.5-20.4 hours) to 8.2 hours (95% CI, 6.7-12.4 hours). Rifampin treatment increased the hydroxybupropion maximum concentration from 395 ng/mL (95% CI, 341-497 ng/mL) to 548 ng/mL (95% CI, 490-638 ng/mL), decreased the area under the concentration-time curve extrapolated to infinity of hydroxybupropion from 14.7 microg x h/mL (95% CI, 12.7-18.4 microg x h/mL) to 8.4 microg x h/mL (95% CI, 7.4-10.2 microg x h/mL), and reduced the elimination half-life of hydroxybupropion from 21.9 hours (95% CI, 20.3-24.0 hours) to 10.7 hours (95% CI, 8.6-14.5 hours). There was no significant difference in the pharmacokinetics of bupropion or hydroxybupropion between white subjects and Chinese subjects before and after treatment with rifampin, once corrected for body weight.


CONCLUSIONS
Rifampin significantly induces CYP2B6 activity in vivo, and the clinical consequences of potential interactions between rifampin and CYP2B6 substrates deserve further investigation. Rifampin appears to induce the elimination of hydroxybupropion. Differences in bupropion pharmacokinetics that were observed between white subjects and Chinese subjects can be attributed to differences in body weight, suggesting that, for a given subject weight, CYP2B6 activity is similar in white subjects and Chinese subjects.
Loboz
Katarzyna K
KK
Faculty of Pharmacy, University of Sydney, Sydney, Australia.
Gross
Annette S
AS
Williams
Kenneth M
KM
Liauw
Winston S
WS
Day
Richard O
RO
Blievernicht
Julia K
JK
Zanger
Ulrich M
UM
McLachlan
Andrew J
AJ
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*; D044466:Asian People; D016642:Bupropion / Q000378:metabolism* / Q000493:pharmacokinetics; D065702:Cytochrome P-450 CYP2B6; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005006:Ethnicity; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism*; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*; D044465:White People
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D012293:Rifampin