title: Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4.
abstract: Fluoxetine and its circulating metabolite norfluoxetine comprise a complex multiple-inhibitor system that causes reversible or time-dependent inhibition of the cytochrome P450 (CYP) family members CYP2D6, CYP3A4, and CYP2C19 in vitro. Although significant inhibition of all three enzymes in vivo was predicted, the areas under the concentration-time curve (AUCs) for midazolam and lovastatin were unaffected by 2-week dosing of fluoxetine, whereas the AUCs of dextromethorphan and omeprazole were increased by 27- and 7.1-fold, respectively. This observed discrepancy between in vitro risk assessment and in vivo drug-drug interaction (DDI) profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions, and CYP3A4 induction. The dynamic models predicted all DDIs with less than twofold error. This study demonstrates that complex DDIs that involve multiple mechanisms, pathways, and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Sager
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Lutz
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen, Seattle, Washington, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Foti
authors.affiliation: Division of Nephrology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: C
authors.initials: C
authors.lastname: Davis
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Kunze
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: N
authors.initials: N
authors.lastname: Isoherranen
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001711:Biotransformation; D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D003915:Dextromethorphan / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008148:Lovastatin / Q000493:pharmacokinetics; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D015233:Models, Statistical; D009853:Omeprazole / Q000493:pharmacokinetics; D013237:Stereoisomerism
chemical_list: D018687:Antidepressive Agents, Second-Generation; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D005473:Fluoxetine; D003915:Dextromethorphan; D008148:Lovastatin; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C036139:norfluoxetine; D009853:Omeprazole; D008874:Midazolam