We have a high-throughput MBI assay using the recombinant Cyps (3A4,Back to the Top
1A2 and 2C9). As a next step, we want to invest our resources to extend
this assay to others enzymes. While there have been some technical
hurdles (substrate specificity and fluorescence interference) for
setting up assays for 2D6 and 2C19, we still lack an adequate
justification for the clinical relevance for 2D6 and 2C19 MBI. On one
hand these are polymorphic and on the other hand, historically, there
have been only handful of marketed compounds that have MBI on 2D6 and
2C19. Given these facts, in your opinion, is it worthwhile to set up
MBI assays for 2D6 and 2C19? If yes, why? If no, are there other
important enzymes (such as 2B1, 2B6, 2E1, 3A5, etc) that we should
focus on in terms of developing MBI assays.
Your comments would be highly appreciated.
Back to the Top
As far as the catalytic mechanism of CYP2D6 and CYP2C19 is concerned,
is no major difference from CYP3A4, 1A2 or 2C9.
So, any of the former two enzymes might be subject to mechanism-based
inhibition due to a new molecular entity.
However, there might be some reason for the lack of report of
clinically-relevant MBI on CYP2D6 and CYP2C19: when any of these
irreversibly inhibited in a given subject, the situation is
close to that of a poor metabolizer. Because of the well-known
of these metabolic enzymes, I would expect any newly developed drug to
already more or less compatible with poor 2D6- and 2C19-metabolizers.
Therefore, most marketed drugs should be more or less insensitive to
to MB inhibition of CYP2D6 or CYP2C19.
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