35
In a study comparing 14-day dosing with WELLBUTRIN
XL Tablets 300 mg once daily to
36
the
immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence
was
37
demonstrated
for peak plasma concentration and area under the curve for bupropion and the
38
3
metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion).
39
Absorption:
Following oral administration of WELLBUTRIN XL Tablets to healthy
40
volunteers,
time to peak plasma concentrations for bupropion was approximately 5 hours and
41
food
did not affect the Cmax or AUC of bupropion.
42
Distribution: In vitro tests shows that bupropion is 84% bound to human plasma
proteins at
43
concentrations
up to 200 mcg/mL. The extent of protein
binding of the hydroxybupropion
44
metabolite
is similar to that for bupropion, whereas the extent of protein binding of the
45
threohydrobupropion
metabolite is about half that seen with bupropion.
46
Metabolism:
Bupropion is extensively metabolized in humans. Three metabolites have been
47
shown
to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl
group
48
of
bupropion, and the amino-alcohol isomers threohydrobupropion and
erythrohydrobupropion,
49
which
are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
50
P450IIB6
(CYP2B6) is the principal isoenzyme involved in the formation of
hydroxybupropion
51
while
cytochrome P450 isoenzymes are not involved in the formation of
threohydrobupropion.
52
Oxidation
of the bupropion side chain results in the formation of a glycine conjugate of
53
meta-chlorobenzoic
acid, which is then excreted as the major urinary metabolite. The potency
54
and
toxicity of the metabolites relative to bupropion have not been fully
characterized. However,
55
it
has been demonstrated in an antidepressant screening test in mice that
hydroxybupropion is
56
one
half as potent as bupropion, while threohydrobupropion and
erythrohydrobupropion are
57
5-fold
less potent than bupropion. This may be
of clinical importance because the plasma
58
concentrations
of the metabolites are as high or higher than those of bupropion.
59
Because bupropion is extensively
metabolized, there is the potential for drug-drug
60
interactions,
particularly with those agents that are metabolized by the cytochrome P450IIB6
61
(CYP2B6)
isoenzyme. Although bupropion is not
metabolized by cytochrome P450IID6
62
(CYP2D6),
there is potential for drug-drug interactions when bupropion is co-administered
63
with
drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
64
In humans, peak plasma concentrations of
hydroxybupropion occur approximately 7 hours
65
after
administration of WELLBUTRIN XL.
Following administration of WELLBUTRIN XL,
66
peak
plasma concentrations of hydroxybupropion are approximately 7 times the peak
level of the
67
parent
drug at steady state. The elimination
half-life of hydroxybupropion is approximately 20
68
(±5)
hours, and its AUC at steady state is about 13 times that of bupropion. The times to peak
69
concentrations
for the erythrohydrobupropion and threohydrobupropion metabolites is similar
70
to
that of the hydroxybupropion metabolite.
However, their elimination half-lives are longer,
71
approximately
33 (±13) hours, respectively, and steady-state AUCs are 1.4 and
72
7
times that of bupropion, respectively.
73
Bupropion and its metabolites exhibit
linear kinetics following chronic administration of 300
74
to
450 mg/day.
2
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