An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4by metabolic intermediate complex formation

An in vitro model is proposed to account for the clinically observed inhibi tion of cytochrome P450 (CYP) 3A that results from administration of clarit hromycin, fluoxetine, or diltiazem. Rates for loss of CYP3A4 enzymatic acti vity resulting from metabolic intermediate complex formation and the concen tration dependencies thereof were determined in vitro for clarithromycin, f luoxetine, and N-desmethyl diltiazem, which is the primary metabolite of di ltiazem. Using the in vitro concentration-dependent rates for loss of activ ity, in vivo rates of CYP3A4 inactivation were predicted for these compound s at a clinically relevant unbound plasma concentration of 0.1 mu M. Based on the predicted rates combined with published rates for in vivo CYP3A degr adation, our model predicts that fluoxetine, clarithromycin, and the primar y metabolite of diltiazem reduce the steady-state concentration of liver CY P3A4 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 d rug that is eliminated exclusively by hepatic CYP3A4 metabolism. These pred icted results are in good agreement with reported clinical data. The major implication of this work is that fluoxetine, clarithromycin, and the primar y metabolite of diltiazem, at clinically relevant concentrations, inactivat e CYP3A4 enzymatic activity at rates sufficient to affect in vivo concentra tions of CYP3A4 and thereby affect the clearance of compounds eliminated by this pathway. We speculate that mechanisms involving substrate-mediated me chanistic inactivation of CYPs play a major role in many clinically observe d drug-drug interactions.