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Vol. 28, Issue 10, 1176-1183, October 2000
Department of Pharmacology and Experimental Therapeutics, Tufts
University School of Medicine, and the Division of Clinical
Pharmacology, New England Medical Center, Boston, Massachusetts
The in vitro biotransformation of bupropion to hydroxybupropion was
studied in human liver microsomes and microsomes containing heterologously expressed human cytochromes P450 (CYP). The mean (±S.E.) Km in four human liver microsomes
was 89 (±14) µM. In microsomes containing cDNA-expressed CYPs,
hydroxybupropion formation was mediated only by CYP2B6 at 50 µM
bupropion (Km 85 µM). A CYP2B6 inhibitory
antibody produced more than 95% inhibition of bupropion hydroxylation
in four human livers. Bupropion hydroxylation activity at 250 µM was
highly correlated with S-mephenytoin
N-demethylation activity (yielding nirvanol), another
CYP2B6-mediated reaction, in a panel of 32 human livers
(r = 0.94). The CYP2B6 content of 12 human livers
highly correlated with bupropion hydroxylation activity
(r = 0.96). Thus bupropion hydroxylation is
mediated almost exclusively by CYP2B6 and can serve as an index
reaction reflecting activity of this isoform. IC50
values for inhibition of a CYP2D6 index reaction (dextromethorphan
O-demethylation) by bupropion and hydroxybupropion were
58 and 74 µM, respectively. This suggests a low inhibitory potency
versus CYP2D6, the clinical importance of which is not established.
Since bupropion is frequently coadministered with other
antidepressants, IC50 values (µM) for inhibition of
bupropion hydroxylation were determined as follows: paroxetine (1.6),
fluvoxamine (6.1), sertraline (3.2), desmethylsertraline (19.9),
fluoxetine (59.5), norfluoxetine (4.2), and nefazodone (25.4).
Bupropion hydroxylation was only weakly inhibited by venlafaxine, O-desmethylvenlafaxine, citalopram, and
desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro
by a number of newer antidepressants suggests the potential for
clinical drug interactions.
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