Inhibition of Cytochrome P450 2C8-mediated Drug Metabolism by the Flavonoid Diosmetin
The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6α-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6α-hydroxypaclit...
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| Veröffentlicht in: | DRUG METABOLISM AND PHARMACOKINETICS 2011-01, Vol.26 (6), p.559-568 |
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| creator | Quintieri, Luigi Palatini, Pietro Moro, Stefano Floreani, Maura |
| description | The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6α-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6α-hydroxypaclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC 50 values 4.25±0.02 and 68.5±3.3μM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13±0.11μM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the Vmax (maximum velocity) and increased the Km value (substrate concentration yielding 50% of Vmax) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with coadministered drugs metabolized by this CYP. |
| doi_str_mv | 10.2133/dmpk.DMPK-11-RG-048 |
| format | Article |
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Diosmetin and hesperetin inhibited 6α-hydroxypaclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC 50 values 4.25±0.02 and 68.5±3.3μM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13±0.11μM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the Vmax (maximum velocity) and increased the Km value (substrate concentration yielding 50% of Vmax) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with coadministered drugs metabolized by this CYP.</description><identifier>ISSN: 1347-4367</identifier><identifier>EISSN: 1880-0920</identifier><identifier>DOI: 10.2133/dmpk.DMPK-11-RG-048</identifier><identifier>PMID: 21791871</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors ; Aryl Hydrocarbon Hydroxylases - metabolism ; Binding Sites ; CYP2C8 inhibition ; Cytochrome P-450 CYP2C8 ; diosmetin ; drug–drug interactions ; Flavonoids - pharmacokinetics ; Flavonoids - pharmacology ; Hesperidin - pharmacokinetics ; Hesperidin - pharmacology ; Humans ; Inactivation, Metabolic ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; molecular docking simulations ; Molecular Dynamics Simulation ; paclitaxel ; Paclitaxel - chemistry ; Paclitaxel - pharmacokinetics ; Paclitaxel - pharmacology</subject><ispartof>DRUG METABOLISM AND PHARMACOKINETICS, 2011-01, Vol.26 (6), p.559-568</ispartof><rights>2011 The Japanese Society for the Study of Xenobiotics</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c613t-4ec2ac674b28e8d1f834272bc836a2670462606bcd41871d9da0d9a731275e523</citedby><cites>FETCH-LOGICAL-c613t-4ec2ac674b28e8d1f834272bc836a2670462606bcd41871d9da0d9a731275e523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21791871$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Quintieri, Luigi</creatorcontrib><creatorcontrib>Palatini, Pietro</creatorcontrib><creatorcontrib>Moro, Stefano</creatorcontrib><creatorcontrib>Floreani, Maura</creatorcontrib><creatorcontrib>Department of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>Department of Pharmacology and Anaesthesiology</creatorcontrib><creatorcontrib>University of Padova</creatorcontrib><creatorcontrib>Molecular Modeling Section (MMS</creatorcontrib><title>Inhibition of Cytochrome P450 2C8-mediated Drug Metabolism by the Flavonoid Diosmetin</title><title>DRUG METABOLISM AND PHARMACOKINETICS</title><addtitle>Drug Metab Pharmacokinet</addtitle><description>The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6α-hydroxy-paclitaxel as a probe reaction. 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The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with coadministered drugs metabolized by this CYP.</description><subject>Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors</subject><subject>Aryl Hydrocarbon Hydroxylases - metabolism</subject><subject>Binding Sites</subject><subject>CYP2C8 inhibition</subject><subject>Cytochrome P-450 CYP2C8</subject><subject>diosmetin</subject><subject>drug–drug interactions</subject><subject>Flavonoids - pharmacokinetics</subject><subject>Flavonoids - pharmacology</subject><subject>Hesperidin - pharmacokinetics</subject><subject>Hesperidin - pharmacology</subject><subject>Humans</subject><subject>Inactivation, Metabolic</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>molecular docking simulations</subject><subject>Molecular Dynamics Simulation</subject><subject>paclitaxel</subject><subject>Paclitaxel - chemistry</subject><subject>Paclitaxel - pharmacokinetics</subject><subject>Paclitaxel - pharmacology</subject><issn>1347-4367</issn><issn>1880-0920</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFO3DAQhq2qFVDgCSpVufUU6rEd2zn0UC2wRQUVIThbjj3bNU3irZ0g7dvX0dIee_H48M-n-T9CPgC9YMD5Zz_sfl1c3t1_rwHqh3VNhX5DTkBrWtOW0bflz4WqBZfqmLzP-ZlSzhvBjsgxA9WCVnBCnm7GbejCFOJYxU212k_RbVMcsLoXDa3YStcD-mAn9NVlmn9WdzjZLvYhD1W3r6YtVte9fYljDCUQYh5wCuMZebexfcbz13lKnq6vHlff6tsf65vV19vaSeBTLdAx66QSHdOoPWw0F0yxzmkuLZOKCskklZ3zYrnWt95S31rFgakGG8ZPyacDd5fi7xnzZIaQHfa9HTHO2bQgOAUFTUnyQ9KlmHPCjdmlMNi0N0DNotMsOs2i0wCYh7UpOsvWx1f-3BUN_3b--iuB9SGwSHK2j2MfRjTPcU5jKW5chGERZhgtVEqXOsswtGna8kgNsnQWbSF9OZCw-HoJmEx2AUdXuAndZHwM_z31Dzl8m-U</recordid><startdate>20110101</startdate><enddate>20110101</enddate><creator>Quintieri, Luigi</creator><creator>Palatini, Pietro</creator><creator>Moro, Stefano</creator><creator>Floreani, Maura</creator><general>Elsevier Ltd</general><general>Japanese Society for the Study of Xenobiotics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20110101</creationdate><title>Inhibition of Cytochrome P450 2C8-mediated Drug Metabolism by the Flavonoid Diosmetin</title><author>Quintieri, Luigi ; Palatini, Pietro ; Moro, Stefano ; Floreani, Maura</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c613t-4ec2ac674b28e8d1f834272bc836a2670462606bcd41871d9da0d9a731275e523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors</topic><topic>Aryl Hydrocarbon Hydroxylases - metabolism</topic><topic>Binding Sites</topic><topic>CYP2C8 inhibition</topic><topic>Cytochrome P-450 CYP2C8</topic><topic>diosmetin</topic><topic>drug–drug interactions</topic><topic>Flavonoids - pharmacokinetics</topic><topic>Flavonoids - pharmacology</topic><topic>Hesperidin - pharmacokinetics</topic><topic>Hesperidin - pharmacology</topic><topic>Humans</topic><topic>Inactivation, Metabolic</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>molecular docking simulations</topic><topic>Molecular Dynamics Simulation</topic><topic>paclitaxel</topic><topic>Paclitaxel - chemistry</topic><topic>Paclitaxel - pharmacokinetics</topic><topic>Paclitaxel - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Quintieri, Luigi</creatorcontrib><creatorcontrib>Palatini, Pietro</creatorcontrib><creatorcontrib>Moro, Stefano</creatorcontrib><creatorcontrib>Floreani, Maura</creatorcontrib><creatorcontrib>Department of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>Department of Pharmacology and Anaesthesiology</creatorcontrib><creatorcontrib>University of Padova</creatorcontrib><creatorcontrib>Molecular Modeling Section (MMS</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>DRUG METABOLISM AND PHARMACOKINETICS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Quintieri, Luigi</au><au>Palatini, Pietro</au><au>Moro, Stefano</au><au>Floreani, Maura</au><aucorp>Department of Pharmaceutical Sciences</aucorp><aucorp>Department of Pharmacology and Anaesthesiology</aucorp><aucorp>University of Padova</aucorp><aucorp>Molecular Modeling Section (MMS</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Cytochrome P450 2C8-mediated Drug Metabolism by the Flavonoid Diosmetin</atitle><jtitle>DRUG METABOLISM AND PHARMACOKINETICS</jtitle><addtitle>Drug Metab Pharmacokinet</addtitle><date>2011-01-01</date><risdate>2011</risdate><volume>26</volume><issue>6</issue><spage>559</spage><epage>568</epage><pages>559-568</pages><issn>1347-4367</issn><eissn>1880-0920</eissn><abstract>The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6α-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6α-hydroxypaclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC 50 values 4.25±0.02 and 68.5±3.3μM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13±0.11μM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the Vmax (maximum velocity) and increased the Km value (substrate concentration yielding 50% of Vmax) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with coadministered drugs metabolized by this CYP.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>21791871</pmid><doi>10.2133/dmpk.DMPK-11-RG-048</doi><tpages>10</tpages></addata></record> |
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| source | MEDLINE; J-STAGE (Japan Science & Technology Information Aggregator, Electronic) Freely Available Titles - Japanese; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors Aryl Hydrocarbon Hydroxylases - metabolism Binding Sites CYP2C8 inhibition Cytochrome P-450 CYP2C8 diosmetin drug–drug interactions Flavonoids - pharmacokinetics Flavonoids - pharmacology Hesperidin - pharmacokinetics Hesperidin - pharmacology Humans Inactivation, Metabolic Microsomes, Liver - drug effects Microsomes, Liver - metabolism molecular docking simulations Molecular Dynamics Simulation paclitaxel Paclitaxel - chemistry Paclitaxel - pharmacokinetics Paclitaxel - pharmacology |
| title | Inhibition of Cytochrome P450 2C8-mediated Drug Metabolism by the Flavonoid Diosmetin |
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