title: In vitro studies on quetiapine metabolism using the substrate depletion approach with focus on drug-drug interactions.
abstract: The metabolism of the atypical antipsychotic quetiapine was investigated by in vitro methods. Pharmacokinetic parameters were determined in human liver microsomes and recombinant cytochrome P450 measuring substrate depletion and product formation. The cytochrome P450 isozymes CYP3A4 and CYP2D6 displayed activity towards quetiapine. The isozyme CYP2D6 played a minor role in the metabolism of quetiapine as CYP3A4 contributed 89% to the overall metabolism. A Km value of 18 microM was determined by substrate depletion, suggesting linear kinetics under therapeutic conditions. Drugs known to inhibit CYP3A4, such as ketoconazole and nefazodone, displayed almost complete inhibition at low concentrations, whereas inhibitors of CYP2D6 do not seem to have a clinically relevant effect.
authors.affiliation: Aarhus University Hospital, Centre for Basic Psychiatric Research, Denmark. jho@psykiatri.aaa.dk
authors.forename: Jørgen
authors.initials: J
authors.lastname: Hasselstrøm
authors.forename: Kristian
authors.initials: K
authors.lastname: Linnet
mesh_terms: D014150:Antipsychotic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D004270:DNA, Circular / Q000378:metabolism; D003987:Dibenzothiazepines / Q000378:metabolism* / Q000493:pharmacokinetics; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D013058:Mass Spectrometry / Q000379:methods; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000069348:Quetiapine Fumarate; D011802:Quinidine / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D004270:DNA, Circular; D003987:Dibenzothiazepines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000069348:Quetiapine Fumarate; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D007654:Ketoconazole