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Vol. 28, Issue 12, 1440-1448, December 2000
GENTEST Corporation, Woburn, Massachusetts
Inhibition of cytochrome P450 catalytic activity is a principal
mechanism for pharmacokinetic drug-drug interactions. Rapid, in vitro
testing for cytochrome P450 inhibition potential is part of the current
paradigm for identifying drug candidates likely to give such
interactions. We have explored the extent that qualitative and
quantitative inhibition parameters are dependent on the cytochrome P450
(CYP) 3A4 probe substrate. Inhibition potential (e.g., IC50 values from 8-point inhibition curves) or activation potential for most
compounds varied dramatically depending on the fluorometric probe
substrates for CYP3A4 [benzyloxyresorufin (BzRes),
7-benzyloxy-4-trifluoromethylcoumarin (BFC), 7-benzyloxyquinoline (BQ),
and dibenzylfluorescein (DBF)]. For 21 compounds that were primarily
inhibitors, the range of IC50 values for the four
substrates varied from 2.1- to 195-fold with an average of 29-fold.
While the rank order of sensitivity among the fluorometric substrates
varied among the individual inhibitors, on average, BFC dealkylation
was the most sensitive to inhibition, while BQ dealkylation was least
sensitive. Partial inhibition was observed with BzRes and BQ but not
for BFC and DBF. BzRes was more prone to activation, whereas
dramatic changes in IC50 values were observed when the BQ
concentration was below the S50. Three different
correlation analyses indicated that IC50 values with BFC,
BQ, and DBF correlated well with each other, whereas the response with
BzRes correlated more weakly with the other substrates. One of these
correlation analyses was extended to the percent inhibition of 10 µM
inhibitor with the standard CYP3A4 probe substrates
testosterone, midazolam, and nifedipine. In this analysis the
responses with BQ, BFC and DBF correlated well with testosterone and
midazolam but more poorly with nifedipine. In the aggregate, BFC and
DBF appear more suitable as an initial screen for CYP3A4 inhibition.
However, the substrate-dependent effects reported here and by others
indicate that all CYP3A4 inhibition data should be interpreted with caution.
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