Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies
Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL...
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| Veröffentlicht in: | Scientific reports 2014-10, Vol.4 (1), p.6587, Article 6587 |
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| description | Curcumin, a specific secondary metabolite of
Curcuma
species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS® immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC
0-540
of EVL by 70.6% and 71.5%, respectively and both dosages reduced the C
max
of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4. |
| doi_str_mv | 10.1038/srep06587 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5377466</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1898153965</sourcerecordid><originalsourceid>FETCH-LOGICAL-c438t-5dd462e1058c4fce8a2e2ee572816ea1c061c0bf5e782811d219540ffc0cfa443</originalsourceid><addsrcrecordid>eNplkEtLAzEUhYMottQu_AMScKUwmudMxoVQii8o1IUuXIU0c6dOHzM1mRnsvzfaWioGQi65H-eeexA6peSKEq6uvYMViaVKDlCXESEjxhk73Ks7qO_9jIQjWSpoeow6THJCeEy6aDx2ZoGLsjZzwFWObeNssyxKvDRuDtlijY2ti9bUkOHh2zPmA3ETcNwWbYVNmWH4jH5qXzdZAf4EHeVm4aG_fXvo9f7uZfgYjcYPT8PBKLKCqzqSWSZiBpRIZUVuQRkGDEAmTNEYDLUkDneSS0hU-KIZo6kUJM8tsbkRgvfQ7UZ31UyWkFko67CIXrkiGF_ryhT6b6cs3vW0arXkSSLiOAicbwVc9dGAr_WsalwZPGuqUkUlT2MZqIsNZV3lQ9L5bgIl-jt-vYs_sGf7lnbkb9gBuNwAPrTKKbi9kf_UvgA1lo5c</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1898153965</pqid></control><display><type>article</type><title>Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Springer Nature OA Free Journals</source><source>Nature Free</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Hsieh, Yow-Wen ; Huang, Ching-Ya ; Yang, Shih-Ying ; Peng, Yu-Hsuan ; Yu, Chung-Ping ; Chao, Pei-Dawn Lee ; Hou, Yu-Chi</creator><creatorcontrib>Hsieh, Yow-Wen ; Huang, Ching-Ya ; Yang, Shih-Ying ; Peng, Yu-Hsuan ; Yu, Chung-Ping ; Chao, Pei-Dawn Lee ; Hou, Yu-Chi</creatorcontrib><description>Curcumin, a specific secondary metabolite of
Curcuma
species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS® immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC
0-540
of EVL by 70.6% and 71.5%, respectively and both dosages reduced the C
max
of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep06587</identifier><identifier>PMID: 25300360</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 64/86 ; 692/308/2778 ; 692/700/565/1436 ; Administration, Oral ; Animals ; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; Bioavailability ; Biological Availability ; Cancer ; Cell Line, Tumor ; Curcumin ; Curcumin - administration & dosage ; Curcumin - pharmacokinetics ; Cytochrome P-450 CYP3A - biosynthesis ; Cytochrome P-450 CYP3A - genetics ; Cytochrome P450 ; Drug Interactions ; Everolimus ; Graft rejection ; Humanities and Social Sciences ; Humans ; Metabolites ; multidisciplinary ; Neoplasms - drug therapy ; Neoplasms - genetics ; Oral administration ; P-Glycoprotein ; Pharmacokinetics ; Rats ; Rodents ; Science ; Sirolimus - administration & dosage ; Sirolimus - analogs & derivatives ; Sirolimus - pharmacokinetics</subject><ispartof>Scientific reports, 2014-10, Vol.4 (1), p.6587, Article 6587</ispartof><rights>The Author(s) 2014</rights><rights>Copyright Nature Publishing Group Oct 2014</rights><rights>Copyright © 2014, Macmillan Publishers Limited. All rights reserved 2014 Macmillan Publishers Limited. All rights reserved</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-5dd462e1058c4fce8a2e2ee572816ea1c061c0bf5e782811d219540ffc0cfa443</citedby><cites>FETCH-LOGICAL-c438t-5dd462e1058c4fce8a2e2ee572816ea1c061c0bf5e782811d219540ffc0cfa443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377466/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377466/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,41119,42188,51575,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25300360$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hsieh, Yow-Wen</creatorcontrib><creatorcontrib>Huang, Ching-Ya</creatorcontrib><creatorcontrib>Yang, Shih-Ying</creatorcontrib><creatorcontrib>Peng, Yu-Hsuan</creatorcontrib><creatorcontrib>Yu, Chung-Ping</creatorcontrib><creatorcontrib>Chao, Pei-Dawn Lee</creatorcontrib><creatorcontrib>Hou, Yu-Chi</creatorcontrib><title>Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Curcumin, a specific secondary metabolite of
Curcuma
species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS® immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC
0-540
of EVL by 70.6% and 71.5%, respectively and both dosages reduced the C
max
of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.</description><subject>13/106</subject><subject>64/86</subject><subject>692/308/2778</subject><subject>692/700/565/1436</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</subject><subject>Bioavailability</subject><subject>Biological Availability</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Curcumin</subject><subject>Curcumin - administration & dosage</subject><subject>Curcumin - pharmacokinetics</subject><subject>Cytochrome P-450 CYP3A - biosynthesis</subject><subject>Cytochrome P-450 CYP3A - genetics</subject><subject>Cytochrome P450</subject><subject>Drug Interactions</subject><subject>Everolimus</subject><subject>Graft rejection</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Metabolites</subject><subject>multidisciplinary</subject><subject>Neoplasms - 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biosynthesis</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</topic><topic>Bioavailability</topic><topic>Biological Availability</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Curcumin</topic><topic>Curcumin - administration & dosage</topic><topic>Curcumin - pharmacokinetics</topic><topic>Cytochrome P-450 CYP3A - biosynthesis</topic><topic>Cytochrome P-450 CYP3A - genetics</topic><topic>Cytochrome P450</topic><topic>Drug Interactions</topic><topic>Everolimus</topic><topic>Graft rejection</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Metabolites</topic><topic>multidisciplinary</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - genetics</topic><topic>Oral administration</topic><topic>P-Glycoprotein</topic><topic>Pharmacokinetics</topic><topic>Rats</topic><topic>Rodents</topic><topic>Science</topic><topic>Sirolimus - administration & dosage</topic><topic>Sirolimus - analogs & derivatives</topic><topic>Sirolimus - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hsieh, Yow-Wen</creatorcontrib><creatorcontrib>Huang, Ching-Ya</creatorcontrib><creatorcontrib>Yang, Shih-Ying</creatorcontrib><creatorcontrib>Peng, Yu-Hsuan</creatorcontrib><creatorcontrib>Yu, Chung-Ping</creatorcontrib><creatorcontrib>Chao, Pei-Dawn Lee</creatorcontrib><creatorcontrib>Hou, Yu-Chi</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hsieh, Yow-Wen</au><au>Huang, Ching-Ya</au><au>Yang, Shih-Ying</au><au>Peng, Yu-Hsuan</au><au>Yu, Chung-Ping</au><au>Chao, Pei-Dawn Lee</au><au>Hou, Yu-Chi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2014-10-10</date><risdate>2014</risdate><volume>4</volume><issue>1</issue><spage>6587</spage><pages>6587-</pages><artnum>6587</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Curcumin, a specific secondary metabolite of
Curcuma
species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS® immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC
0-540
of EVL by 70.6% and 71.5%, respectively and both dosages reduced the C
max
of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25300360</pmid><doi>10.1038/srep06587</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 13/106 64/86 692/308/2778 692/700/565/1436 Administration, Oral Animals ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis ATP-Binding Cassette, Sub-Family B, Member 1 - genetics Bioavailability Biological Availability Cancer Cell Line, Tumor Curcumin Curcumin - administration & dosage Curcumin - pharmacokinetics Cytochrome P-450 CYP3A - biosynthesis Cytochrome P-450 CYP3A - genetics Cytochrome P450 Drug Interactions Everolimus Graft rejection Humanities and Social Sciences Humans Metabolites multidisciplinary Neoplasms - drug therapy Neoplasms - genetics Oral administration P-Glycoprotein Pharmacokinetics Rats Rodents Science Sirolimus - administration & dosage Sirolimus - analogs & derivatives Sirolimus - pharmacokinetics |
| title | Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies |
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