Effect of St John's Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme
CONTEXT St John's wort is a popular herbal product used to treat depression but it has been implicated in drug interactions. OBJECTIVE To assess the potential of St John's wort administration to alter the activity of the cytochrome P450 (CYP) enzymes extensively involved in drug metabolism...
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| Veröffentlicht in: | JAMA : the journal of the American Medical Association 2003-09, Vol.290 (11), p.1500-1504 |
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| creator | Markowitz, John S Donovan, Jennifer L DeVane, C. Lindsay Taylor, Robin M Ruan, Ying Wang, Jun-Sheng Chavin, Kenneth D |
| description | CONTEXT St John's wort is a popular herbal product used to treat depression
but it has been implicated in drug interactions. OBJECTIVE To assess the potential of St John's wort administration to alter the
activity of the cytochrome P450 (CYP) enzymes extensively involved in drug
metabolism. DESIGN, SETTING, AND PARTICIPANTS Open-label crossover study with fixed treatment order conducted March
2002 to February 2003 in a US general clinical research center involving 12
healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after
14 days of administration of St John's wort. INTERVENTION Participants were given probe drugs (30 mg of dextromethorphan and 2
mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After
a minimum 7-day washout period, participants began taking one 300-mg tablet
3 times per day. After 14 days of St John's wort administration, participants
were given the probe drugs along with 1 St John's wort tablet to establish
postadministration CYP activity; the St John's wort dosing regimen was continued
for 48 hours. MAIN OUTCOME MEASURES Changes in plasma pharmacokinetics of alprazolam as a probe for CYP
3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan,
in urine as a probe for CYP 2D6 activity. RESULTS A 2-fold decrease in the area under the curve for alprazolam plasma
concentration vs time (P |
| doi_str_mv | 10.1001/jama.290.11.1500 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_journals_211353964</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><ama_id>197306</ama_id><sourcerecordid>419776391</sourcerecordid><originalsourceid>FETCH-LOGICAL-a420t-4dade29b05d8c253e9fce86526486608290097d7bb38f50620a477a436ba61653</originalsourceid><addsrcrecordid>eNpFkE1PwzAMhiMEYmNwhwuKkBCnDuezyXEaA4aGQOLrWKVtCp3WZjTtofx6gjY0Xyz7fWzLL0KnBMYEgFwvTWXGVIeKjIkA2ENDIpiKmNBqHw0BtIpirvgAHXm_hBCExYdoQBihWmsyRO-zorBZi12BX1r84L7qK48_XBM6Nb5puk_8aFuTulXpK5z2eF7nXdaWQQwT07512VfjKoufuQDMJhzP6p--ssfooDArb0-2eYTebmev0_to8XQ3n04WkeEU2ojnJrdUpyBylVHBrC4yq6SgkispQYXXQMd5nKZMFQIkBcPj2HAmUyOJFGyELjZ714377qxvk6XrmjqcTCghTDAteYDOt1CXVjZP1k1ZmaZP_l0IwOUWMD4zq6IxdVb6HScIA67-uLMNF2zfqTpmINkvmdNwZg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>211353964</pqid></control><display><type>article</type><title>Effect of St John's Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme</title><source>MEDLINE</source><source>American Medical Association Journals</source><creator>Markowitz, John S ; Donovan, Jennifer L ; DeVane, C. Lindsay ; Taylor, Robin M ; Ruan, Ying ; Wang, Jun-Sheng ; Chavin, Kenneth D</creator><creatorcontrib>Markowitz, John S ; Donovan, Jennifer L ; DeVane, C. Lindsay ; Taylor, Robin M ; Ruan, Ying ; Wang, Jun-Sheng ; Chavin, Kenneth D</creatorcontrib><description>CONTEXT St John's wort is a popular herbal product used to treat depression
but it has been implicated in drug interactions. OBJECTIVE To assess the potential of St John's wort administration to alter the
activity of the cytochrome P450 (CYP) enzymes extensively involved in drug
metabolism. DESIGN, SETTING, AND PARTICIPANTS Open-label crossover study with fixed treatment order conducted March
2002 to February 2003 in a US general clinical research center involving 12
healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after
14 days of administration of St John's wort. INTERVENTION Participants were given probe drugs (30 mg of dextromethorphan and 2
mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After
a minimum 7-day washout period, participants began taking one 300-mg tablet
3 times per day. After 14 days of St John's wort administration, participants
were given the probe drugs along with 1 St John's wort tablet to establish
postadministration CYP activity; the St John's wort dosing regimen was continued
for 48 hours. MAIN OUTCOME MEASURES Changes in plasma pharmacokinetics of alprazolam as a probe for CYP
3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan,
in urine as a probe for CYP 2D6 activity. RESULTS A 2-fold decrease in the area under the curve for alprazolam plasma
concentration vs time (P<.001) and a 2-fold increase
in alprazolam clearance (P<.001) were observed
following St John's wort administration. Alprazolam elimination half-life
was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan
to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St
John's wort administration (P = .26). CONCLUSIONS A 14-day course of St John's wort administration significantly induced
the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics.
This suggests that long-term administration of St John's wort may result in
diminished clinical effectiveness or increased dosage requirements for all
CYP 3A4 substrates, which represent at least 50% of all marketed medications.</description><identifier>ISSN: 0098-7484</identifier><identifier>EISSN: 1538-3598</identifier><identifier>DOI: 10.1001/jama.290.11.1500</identifier><identifier>PMID: 13129991</identifier><identifier>CODEN: JAMAAP</identifier><language>eng</language><publisher>Chicago, IL: American Medical Association</publisher><subject>Adult ; Alprazolam - pharmacokinetics ; Biological and medical sciences ; Cross-Over Studies ; Cytochrome P-450 CYP2D6 - metabolism ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System - metabolism ; Dextromethorphan - metabolism ; Drug Interactions ; Drugs ; Enzyme Induction - drug effects ; Enzymes ; Female ; Folk medicine ; Humans ; Hypericum ; Male ; Medical sciences ; Metabolism ; Miscellaneous ; Pharmacology. Drug treatments ; Plant Extracts - pharmacology ; Substrate Specificity</subject><ispartof>JAMA : the journal of the American Medical Association, 2003-09, Vol.290 (11), p.1500-1504</ispartof><rights>2004 INIST-CNRS</rights><rights>Copyright American Medical Association Sep 17, 2003</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a420t-4dade29b05d8c253e9fce86526486608290097d7bb38f50620a477a436ba61653</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jamanetwork.com/journals/jama/articlepdf/10.1001/jama.290.11.1500$$EPDF$$P50$$Gama$$H</linktopdf><linktohtml>$$Uhttps://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.290.11.1500$$EHTML$$P50$$Gama$$H</linktohtml><link.rule.ids>64,314,780,784,3340,27924,27925,76489,76492</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15130481$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/13129991$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Markowitz, John S</creatorcontrib><creatorcontrib>Donovan, Jennifer L</creatorcontrib><creatorcontrib>DeVane, C. Lindsay</creatorcontrib><creatorcontrib>Taylor, Robin M</creatorcontrib><creatorcontrib>Ruan, Ying</creatorcontrib><creatorcontrib>Wang, Jun-Sheng</creatorcontrib><creatorcontrib>Chavin, Kenneth D</creatorcontrib><title>Effect of St John's Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme</title><title>JAMA : the journal of the American Medical Association</title><addtitle>JAMA</addtitle><description>CONTEXT St John's wort is a popular herbal product used to treat depression
but it has been implicated in drug interactions. OBJECTIVE To assess the potential of St John's wort administration to alter the
activity of the cytochrome P450 (CYP) enzymes extensively involved in drug
metabolism. DESIGN, SETTING, AND PARTICIPANTS Open-label crossover study with fixed treatment order conducted March
2002 to February 2003 in a US general clinical research center involving 12
healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after
14 days of administration of St John's wort. INTERVENTION Participants were given probe drugs (30 mg of dextromethorphan and 2
mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After
a minimum 7-day washout period, participants began taking one 300-mg tablet
3 times per day. After 14 days of St John's wort administration, participants
were given the probe drugs along with 1 St John's wort tablet to establish
postadministration CYP activity; the St John's wort dosing regimen was continued
for 48 hours. MAIN OUTCOME MEASURES Changes in plasma pharmacokinetics of alprazolam as a probe for CYP
3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan,
in urine as a probe for CYP 2D6 activity. RESULTS A 2-fold decrease in the area under the curve for alprazolam plasma
concentration vs time (P<.001) and a 2-fold increase
in alprazolam clearance (P<.001) were observed
following St John's wort administration. Alprazolam elimination half-life
was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan
to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St
John's wort administration (P = .26). CONCLUSIONS A 14-day course of St John's wort administration significantly induced
the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics.
This suggests that long-term administration of St John's wort may result in
diminished clinical effectiveness or increased dosage requirements for all
CYP 3A4 substrates, which represent at least 50% of all marketed medications.</description><subject>Adult</subject><subject>Alprazolam - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Cross-Over Studies</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Dextromethorphan - metabolism</subject><subject>Drug Interactions</subject><subject>Drugs</subject><subject>Enzyme Induction - drug effects</subject><subject>Enzymes</subject><subject>Female</subject><subject>Folk medicine</subject><subject>Humans</subject><subject>Hypericum</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Miscellaneous</subject><subject>Pharmacology. Drug treatments</subject><subject>Plant Extracts - pharmacology</subject><subject>Substrate Specificity</subject><issn>0098-7484</issn><issn>1538-3598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1PwzAMhiMEYmNwhwuKkBCnDuezyXEaA4aGQOLrWKVtCp3WZjTtofx6gjY0Xyz7fWzLL0KnBMYEgFwvTWXGVIeKjIkA2ENDIpiKmNBqHw0BtIpirvgAHXm_hBCExYdoQBihWmsyRO-zorBZi12BX1r84L7qK48_XBM6Nb5puk_8aFuTulXpK5z2eF7nXdaWQQwT07512VfjKoufuQDMJhzP6p--ssfooDArb0-2eYTebmev0_to8XQ3n04WkeEU2ojnJrdUpyBylVHBrC4yq6SgkispQYXXQMd5nKZMFQIkBcPj2HAmUyOJFGyELjZ714377qxvk6XrmjqcTCghTDAteYDOt1CXVjZP1k1ZmaZP_l0IwOUWMD4zq6IxdVb6HScIA67-uLMNF2zfqTpmINkvmdNwZg</recordid><startdate>20030917</startdate><enddate>20030917</enddate><creator>Markowitz, John S</creator><creator>Donovan, Jennifer L</creator><creator>DeVane, C. Lindsay</creator><creator>Taylor, Robin M</creator><creator>Ruan, Ying</creator><creator>Wang, Jun-Sheng</creator><creator>Chavin, Kenneth D</creator><general>American Medical Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QL</scope><scope>7QP</scope><scope>7TK</scope><scope>7TS</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20030917</creationdate><title>Effect of St John's Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme</title><author>Markowitz, John S ; Donovan, Jennifer L ; DeVane, C. Lindsay ; Taylor, Robin M ; Ruan, Ying ; Wang, Jun-Sheng ; Chavin, Kenneth D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a420t-4dade29b05d8c253e9fce86526486608290097d7bb38f50620a477a436ba61653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Adult</topic><topic>Alprazolam - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Cross-Over Studies</topic><topic>Cytochrome P-450 CYP2D6 - metabolism</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Dextromethorphan - metabolism</topic><topic>Drug Interactions</topic><topic>Drugs</topic><topic>Enzyme Induction - drug effects</topic><topic>Enzymes</topic><topic>Female</topic><topic>Folk medicine</topic><topic>Humans</topic><topic>Hypericum</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Miscellaneous</topic><topic>Pharmacology. Drug treatments</topic><topic>Plant Extracts - pharmacology</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Markowitz, John S</creatorcontrib><creatorcontrib>Donovan, Jennifer L</creatorcontrib><creatorcontrib>DeVane, C. Lindsay</creatorcontrib><creatorcontrib>Taylor, Robin M</creatorcontrib><creatorcontrib>Ruan, Ying</creatorcontrib><creatorcontrib>Wang, Jun-Sheng</creatorcontrib><creatorcontrib>Chavin, Kenneth D</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>JAMA : the journal of the American Medical Association</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Markowitz, John S</au><au>Donovan, Jennifer L</au><au>DeVane, C. Lindsay</au><au>Taylor, Robin M</au><au>Ruan, Ying</au><au>Wang, Jun-Sheng</au><au>Chavin, Kenneth D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of St John's Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme</atitle><jtitle>JAMA : the journal of the American Medical Association</jtitle><addtitle>JAMA</addtitle><date>2003-09-17</date><risdate>2003</risdate><volume>290</volume><issue>11</issue><spage>1500</spage><epage>1504</epage><pages>1500-1504</pages><issn>0098-7484</issn><eissn>1538-3598</eissn><coden>JAMAAP</coden><abstract>CONTEXT St John's wort is a popular herbal product used to treat depression
but it has been implicated in drug interactions. OBJECTIVE To assess the potential of St John's wort administration to alter the
activity of the cytochrome P450 (CYP) enzymes extensively involved in drug
metabolism. DESIGN, SETTING, AND PARTICIPANTS Open-label crossover study with fixed treatment order conducted March
2002 to February 2003 in a US general clinical research center involving 12
healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after
14 days of administration of St John's wort. INTERVENTION Participants were given probe drugs (30 mg of dextromethorphan and 2
mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After
a minimum 7-day washout period, participants began taking one 300-mg tablet
3 times per day. After 14 days of St John's wort administration, participants
were given the probe drugs along with 1 St John's wort tablet to establish
postadministration CYP activity; the St John's wort dosing regimen was continued
for 48 hours. MAIN OUTCOME MEASURES Changes in plasma pharmacokinetics of alprazolam as a probe for CYP
3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan,
in urine as a probe for CYP 2D6 activity. RESULTS A 2-fold decrease in the area under the curve for alprazolam plasma
concentration vs time (P<.001) and a 2-fold increase
in alprazolam clearance (P<.001) were observed
following St John's wort administration. Alprazolam elimination half-life
was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan
to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St
John's wort administration (P = .26). CONCLUSIONS A 14-day course of St John's wort administration significantly induced
the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics.
This suggests that long-term administration of St John's wort may result in
diminished clinical effectiveness or increased dosage requirements for all
CYP 3A4 substrates, which represent at least 50% of all marketed medications.</abstract><cop>Chicago, IL</cop><pub>American Medical Association</pub><pmid>13129991</pmid><doi>10.1001/jama.290.11.1500</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0098-7484 |
| ispartof | JAMA : the journal of the American Medical Association, 2003-09, Vol.290 (11), p.1500-1504 |
| issn | 0098-7484 1538-3598 |
| language | eng |
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| source | MEDLINE; American Medical Association Journals |
| subjects | Adult Alprazolam - pharmacokinetics Biological and medical sciences Cross-Over Studies Cytochrome P-450 CYP2D6 - metabolism Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - metabolism Dextromethorphan - metabolism Drug Interactions Drugs Enzyme Induction - drug effects Enzymes Female Folk medicine Humans Hypericum Male Medical sciences Metabolism Miscellaneous Pharmacology. Drug treatments Plant Extracts - pharmacology Substrate Specificity |
| title | Effect of St John's Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme |
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