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Vol. 28, Issue 9, 1031-1037, September 2000
Division of Clinical Pharmacology, Department of Medicine, Indiana
University School of Medicine, Indianapolis, Indiana
An in vitro model is proposed to account for the clinically
observed inhibition of cytochrome P450 (CYP) 3A that results from administration of clarithromycin, fluoxetine, or diltiazem. Rates for
loss of CYP3A4 enzymatic activity resulting from metabolic intermediate
complex formation and the concentration dependencies thereof
were determined in vitro for clarithromycin, fluoxetine, and
N-desmethyl diltiazem, which is the primary metabolite
of diltiazem. Using the in vitro concentration-dependent rates for loss
of activity, in vivo rates of CYP3A4 inactivation were predicted for
these compounds at a clinically relevant unbound plasma concentration of 0.1 µM. Based on the predicted rates combined with published rates
for in vivo CYP3A degradation, our model predicts that fluoxetine, clarithromycin, and the primary metabolite of diltiazem reduce the
steady-state concentration of liver CYP3A4 to approximately 72, 39, or
21% of initial levels, respectively. These reductions correspond to
1.4-, 2.6-, or 4.7-fold increases, respectively, in the area under the
plasma concentration-time curve of a coadministered drug that is
eliminated exclusively by hepatic CYP3A4 metabolism. These predicted
results are in good agreement with reported clinical data. The major
implication of this work is that fluoxetine, clarithromycin, and the
primary metabolite of diltiazem, at clinically relevant concentrations,
inactivate CYP3A4 enzymatic activity at rates sufficient to affect in
vivo concentrations of CYP3A4 and thereby affect the clearance of
compounds eliminated by this pathway. We speculate that mechanisms
involving substrate-mediated mechanistic inactivation of CYPs play a
major role in many clinically observed drug-drug interactions.
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