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Vol. 28, Issue 3, 360-366, March 2000
Department of Drug Metabolism, Merck Research Laboratories, Rahway,
New Jersey (R.W.W., D.J.N., N.L., A.Y.H.L.); and Department of
Medicinal Chemistry, University of Washington, Seattle, Washington
(W.M.A.)
Testosterone, terfenadine, midazolam, and nifedipine, four commonly
used substrates for human cytochrome P-450 3A4 (CYP3A4), were
studied in pairs in human liver microsomes and in microsomes from cells
containing recombinant human CYP3A4 and P-450 reductase, to investigate
in vitro substrate-substrate interaction with CYP3A4. The interaction
patterns between compounds with CYP3A4 were found to be
substrate-dependent. Mutual inhibition, partial inhibition, and
activation were observed in the testosterone-terfenadine, testosterone-midazolam, or terfenadine-midazolam interactions. However,
the most unusual result was the interaction between testosterone and
nifedipine. Although nifedipine inhibited testosterone
6
-hydroxylation in a concentration-dependent manner, testosterone
did not inhibit nifedipine oxidation. Furthermore, the effect of
testosterone and 7,8-benzoflavone on midazolam 1'-hydroxylation and
4-hydroxylation demonstrated different regiospecificities. These
results may be explained by a model in which multiple substrates or
ligands can bind concurrently to the active site of a single CYP3A4
molecule. However, the contribution of separate allosteric sites and
conformational heterogeneity to the atypical kinetics of CYP3A4 can not
be ruled out in this model.
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