title: An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation.
abstract: 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 microM. 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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Mayhew
authors.forename: D R
authors.initials: DR
authors.lastname: Jones
authors.forename: S D
authors.initials: SD
authors.lastname: Hall
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D017291:Clarithromycin / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004110:Diltiazem / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000493:pharmacokinetics; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008954:Models, Biological; D011237:Predictive Value of Tests; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D017291:Clarithromycin; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004110:Diltiazem; D005473:Fluoxetine; D006899:Mixed Function Oxygenases; D017367:Selective Serotonin Reuptake Inhibitors; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human