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Vol. 27, Issue 5, 596-599, May 1999
Departments of Medicinal Chemistry (K.L.K., W.N.H.) and
Pharmaceutics (M.A.G., K.E.T.), School of Pharmacy, University of
Washington, Seattle, Washington
The purpose of this work was to evaluate the effect of mutual
unbound inhibitor and unbound enzyme depletion on the potency of three
antifungal cytochrome P-450 (CYP)3A inhibitors with over 1000-fold range in enzyme affinity. Incubations were performed with human liver microsomal protein concentrations that varied from 25 to 1000 µg/ml. The effect of each inhibitor was evaluated using
midazolam as a CYP3A probe. Clotrimazole was found to be a tight
binding inhibitor of CYP3A with a Ki of 250 pM. Analysis of percent inhibition data by stepwise linear regression
for the matrix of inhibitor and enzyme concentrations used showed that protein concentrations predicted the percent inhibition by clotrimazole (r2 = 0.60, p < .001). When
clotrimazole concentrations were added to the model, the r2
improved to 0.81, p = .003. Clotrimazole
concentrations alone were not a significant predictor of percent
inhibition (r2 = 0.21, p = .08). For
ketoconazole, protein concentrations provided a weak prediction of the
percent inhibition (r2 = 0.39, p = .006). Conversely, ketoconazole concentrations alone were a good
predictor of percent inhibition (r2 = 0.55, p < .001). In contrast to results with
clotrimazole and ketoconazole, percent inhibition by fluconazole was
not dependent on protein concentrations (r2 = 0.06, p = .39). We conclude that microsomal inhibitory
potency can be affected by incubation conditions that deplete the
unbound concentration of inhibitor available to the enzyme. This may
introduce serious error into a quantitative prediction of an in vivo
drug-drug interaction based on an in vitro derived
Ki value.
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