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      Comparative Cytochrome P450 In Vitro Inhibition by Atypical Antipsychotic Drugs

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          Abstract

          The goal of this study was to assess in human liver microsomes the inhibitory capacity of commonly used antipsychotics on the most prominent CYP450 drug metabolizing enzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A). Chlorpromazine was the only antipsychotic that inhibited CYP1A2 activity (IC 50 = 9.5  μ M), whilst levomepromazine, chlorpromazine, and thioridazine significantly decreased CYP2D6-mediated formation of 1′-hydroxybufuralol (IC 50 range, 3.5–25.5  μ M). Olanzapine inhibited CYP3A-catalyzed production of 1′, and 4′-hydroxymidazolam (IC 50 = 14.65 and 42.20  μ M, resp.). In contrast, risperidone (IC 50 = 20.7  μ M) and levomepromazine (IC 50 = 30  μ M) showed selectivity towards the inhibition of midazolam 1′-hydroxylation reaction, and haloperidol did so towards 4′-hydroxylation (IC 50 of 2.76  μ M). Thioridazine displayed a K i of 1.75  μ M and an inhibitory potency of 1.57 on CYP2D6, suggesting a potential to induce in vivo interactions. However, with this exception, and given the observed K i values, the potential of the assayed antipsychotics to produce clinically significant inhibitions of CYP450 isoforms in vivo seems limited.

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          Most cited references40

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          IC50-to-Ki: a web-based tool for converting IC50 to Ki values for inhibitors of enzyme activity and ligand binding

          A new web-server tool estimates K i values from experimentally determined IC 50 values for inhibitors of enzymes and of binding reactions between macromolecules (e.g. proteins, polynucleic acids) and ligands. This converter was developed to enable end users to help gauge the quality of the underlying assumptions used in these calculations which depend on the type of mechanism of inhibitor action and the concentrations of the interacting molecular species. Additional calculations are performed for nonclassical, tightly bound inhibitors of enzyme-substrate or of macromolecule-ligand systems in which free, rather than total concentrations of the reacting species are required. Required user-defined input values include the total enzyme (or another target molecule) and substrate (or ligand) concentrations, the K m of the enzyme-substrate (or the K d of the target-ligand) reaction, and the IC 50 value. Assumptions and caveats for these calculations are discussed along with examples taken from the literature. The host database for this converter contains kinetic constants and other data for inhibitors of the proteolytic clostridial neurotoxins (http://botdb.abcc.ncifcrf.gov/toxin/kiConverter.jsp).
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            Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.

            Accumulating evidence indicates that CYP2C9 ranks amongst the most important drug metabolizing enzymes in humans. Substrates for CYP2C9 include fluoxetine, losartan, phenytoin, tolbutamide, torsemide, S-warfarin, and numerous NSAIDs. CYP2C9 activity in vivo is inducible by rifampicin. Evidence suggests that CYP2C9 substrates may also be induced variably by carbamazepine, ethanol and phenobarbitone. Apart from the mutual competitive inhibition which may occur between alternate substrates, numerous other drugs have been shown to inhibit CYP2C9 activity in vivo and/or in vitro. Clinically significant inhibition may occur with coadministration of amiodarone, fluconazole, phenylbutazone, sulphinpyrazone, sulphaphenazole and certain other sulphonamides. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino acid residues 144 (Arg144Cys) and 359 (Ile359Leu) of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, although the frequency of this allele is relatively low. Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. Individualisation of dose is essential for those CYP2C9 substrates with a narrow therapeutic index.
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              Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test.

              In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (rs = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. N1- and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.
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                Author and article information

                Journal
                ISRN Pharmacol
                ISRN Pharmacol
                ISRN.PHARMACOLOGY
                ISRN Pharmacology
                Hindawi Publishing Corporation
                2090-5165
                2090-5173
                2013
                13 February 2013
                : 2013
                : 792456
                Affiliations
                Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Av. Elvas s/n, 06071 Badajoz, Spain
                Author notes
                *Guillermo Gervasini: ggervasi@ 123456unex.es

                Academic Editors: K. Cimanga, G. Froldi, D. K. Miller, R. Villalobos-Molina, and T. B. Vree

                Article
                10.1155/2013/792456
                3586484
                23476805
                7dc7144e-72a3-43f8-8423-1ecc19bcb05b
                Copyright © 2013 Guillermo Gervasini et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 December 2012
                : 8 January 2013
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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