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NDA 20-358 |
17 |
metabolite 306U73 was 2 times more potent
than the parent in decreasing noradrenergic firing rate in rats (and metabolite
494U73) had no effect at a dose about 5 x that of the parent). It was also stated that B, although not
metabolites 306U73 and 494U73, decreased dopaminergic firing rate when given
i.v., but the doses tested were not stated.
b)
As
shown in the attached table taken from the submission of 1/28/93, metabolites
306U73 and 494U73 ranged from being approximately equipotent to being 20x less
potent than B in blocking neurotransmitter uptake in vitro.)
However, note that potencies were relatively low in all cases).
c)
The
i.p. LD50 values for 3 metabolites were lower than that of parent
compound in mice. (Values included
in the table of anti-tetrabenazine results).
Thus, the relative potency values of parent and
metabolites given in the proposed labeling are misleading; in fact I do not
think it warranted even to imply that the metabolites are less potent than the
parent compound based on the data provided. A more accurate picture might be to leave out the statements
concerning relative potency (e.g., from "however" on line 114 to
"bupropion" on line 116) so that this section might read:
"...These metabolites of bupropion are pharmacologically active although
their potency and toxicity relative to bupropion have not been fully
characterized. They may be of
clinical importance because their plasma concentrations are higher than those
of bupropion." (I have left
out the phrase "in chronic use" from the last sentence; are these
metabolites not quantitatively significant in acute or subacute use?).
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