Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P-450 2C9 and Metabolic Inhibitors
Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17α‐ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes...
Gespeichert in:
| Veröffentlicht in: | Journal of clinical pharmacology 1997-03, Vol.37 (3), p.193-200 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 200 |
|---|---|
| container_issue | 3 |
| container_start_page | 193 |
| container_title | Journal of clinical pharmacology |
| container_volume | 37 |
| creator | Schmider, Jürgen Greenblatt, David J. von Moltke, Lisa L. Karsov, Dmitri Vena, Richard Friedman, Hylar L. Shader, Richard I. |
| description | Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17α‐ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 μmol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 μmol/L (range, 1.8–8.3 μmol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60–91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. α‐Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations |
| doi_str_mv | 10.1002/j.1552-4604.1997.tb04781.x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_78917152</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>78917152</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5041-ebd2bd112b863256712e6d70bbd913d2916df7677943323d7d9871d5f64fe1ab3</originalsourceid><addsrcrecordid>eNqVkFuP1CAUxxujWcfVj2BCjPGtlUMplH3Sbca9uOrErJc3QgvNMLZlBSY78-2lmcm8-wQ5_8uBX5a9AVwAxuT9poCqIjllmBYgBC9iiymvodg9yRYn6Wm2wFhATjjGz7MXIWwwBkYrOMvOBK4FJbDIHi-ti15NoXd-VNG6CbkefTFhHroBRYeWcW2n_YCW80zbNLyZ0E8bvbtA92uDvrvBzKFmH1239m40aJXTCiPSCKQmndqiat1guxRc29ZG58PL7FmvhmBeHc_z7Men5X1znd99u7ppPt7lXYUp5KbVpNUApK1ZSSrGgRimOW5bLaDURADTPWecC1qWpNRci5qDrnpGewOqLc-zd4feB-_-btO35GhDZ4ZBTcZtg-S1AA4VScaLg7HzLgRvevng7aj8XgKWM3W5kTNaOaOVM3V5pC53Kfz6uGXbjkafokfMSX971FXo1NAntp0NJxthZU0FTrYPB9ujHcz-Px4gb5vV9XxNFfmhwoZodqcK5f9IxkteyV9fr-Tt6nNzydhvCeU_-CetbA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>78917152</pqid></control><display><type>article</type><title>Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P-450 2C9 and Metabolic Inhibitors</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Schmider, Jürgen ; Greenblatt, David J. ; von Moltke, Lisa L. ; Karsov, Dmitri ; Vena, Richard ; Friedman, Hylar L. ; Shader, Richard I.</creator><creatorcontrib>Schmider, Jürgen ; Greenblatt, David J. ; von Moltke, Lisa L. ; Karsov, Dmitri ; Vena, Richard ; Friedman, Hylar L. ; Shader, Richard I.</creatorcontrib><description>Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17α‐ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 μmol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 μmol/L (range, 1.8–8.3 μmol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60–91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. α‐Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations <2 μmol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (<20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 μmol/L (range, 0.7–3.2 μmol/L) and an average Emax of 90% (range, 77–100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 μmol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/j.1552-4604.1997.tb04781.x</identifier><identifier>PMID: 9089421</identifier><identifier>CODEN: JCPCBR</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adult ; Antifungal Agents - pharmacokinetics ; Biological and medical sciences ; Biotransformation ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - physiology ; Estradiol Congeners - metabolism ; Estradiol Congeners - pharmacokinetics ; Ethinyl Estradiol - metabolism ; Female ; Fluconazole - pharmacokinetics ; Genital system. Reproduction ; Humans ; Itraconazole - pharmacokinetics ; Ketoconazole - pharmacokinetics ; Medical sciences ; Mestranol - metabolism ; Mestranol - pharmacokinetics ; Microsomes, Liver - enzymology ; Microsomes, Liver - physiology ; Pharmacology. Drug treatments</subject><ispartof>Journal of clinical pharmacology, 1997-03, Vol.37 (3), p.193-200</ispartof><rights>1997 American College of Clinical Pharmacology</rights><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5041-ebd2bd112b863256712e6d70bbd913d2916df7677943323d7d9871d5f64fe1ab3</citedby><cites>FETCH-LOGICAL-c5041-ebd2bd112b863256712e6d70bbd913d2916df7677943323d7d9871d5f64fe1ab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fj.1552-4604.1997.tb04781.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fj.1552-4604.1997.tb04781.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2638490$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9089421$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schmider, Jürgen</creatorcontrib><creatorcontrib>Greenblatt, David J.</creatorcontrib><creatorcontrib>von Moltke, Lisa L.</creatorcontrib><creatorcontrib>Karsov, Dmitri</creatorcontrib><creatorcontrib>Vena, Richard</creatorcontrib><creatorcontrib>Friedman, Hylar L.</creatorcontrib><creatorcontrib>Shader, Richard I.</creatorcontrib><title>Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P-450 2C9 and Metabolic Inhibitors</title><title>Journal of clinical pharmacology</title><addtitle>J Clin Pharmacol</addtitle><description>Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17α‐ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 μmol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 μmol/L (range, 1.8–8.3 μmol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60–91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. α‐Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations <2 μmol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (<20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 μmol/L (range, 0.7–3.2 μmol/L) and an average Emax of 90% (range, 77–100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 μmol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.</description><subject>Adult</subject><subject>Antifungal Agents - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Cells, Cultured</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - physiology</subject><subject>Estradiol Congeners - metabolism</subject><subject>Estradiol Congeners - pharmacokinetics</subject><subject>Ethinyl Estradiol - metabolism</subject><subject>Female</subject><subject>Fluconazole - pharmacokinetics</subject><subject>Genital system. Reproduction</subject><subject>Humans</subject><subject>Itraconazole - pharmacokinetics</subject><subject>Ketoconazole - pharmacokinetics</subject><subject>Medical sciences</subject><subject>Mestranol - metabolism</subject><subject>Mestranol - pharmacokinetics</subject><subject>Microsomes, Liver - enzymology</subject><subject>Microsomes, Liver - physiology</subject><subject>Pharmacology. Drug treatments</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkFuP1CAUxxujWcfVj2BCjPGtlUMplH3Sbca9uOrErJc3QgvNMLZlBSY78-2lmcm8-wQ5_8uBX5a9AVwAxuT9poCqIjllmBYgBC9iiymvodg9yRYn6Wm2wFhATjjGz7MXIWwwBkYrOMvOBK4FJbDIHi-ti15NoXd-VNG6CbkefTFhHroBRYeWcW2n_YCW80zbNLyZ0E8bvbtA92uDvrvBzKFmH1239m40aJXTCiPSCKQmndqiat1guxRc29ZG58PL7FmvhmBeHc_z7Men5X1znd99u7ppPt7lXYUp5KbVpNUApK1ZSSrGgRimOW5bLaDURADTPWecC1qWpNRci5qDrnpGewOqLc-zd4feB-_-btO35GhDZ4ZBTcZtg-S1AA4VScaLg7HzLgRvevng7aj8XgKWM3W5kTNaOaOVM3V5pC53Kfz6uGXbjkafokfMSX971FXo1NAntp0NJxthZU0FTrYPB9ujHcz-Px4gb5vV9XxNFfmhwoZodqcK5f9IxkteyV9fr-Tt6nNzydhvCeU_-CetbA</recordid><startdate>199703</startdate><enddate>199703</enddate><creator>Schmider, Jürgen</creator><creator>Greenblatt, David J.</creator><creator>von Moltke, Lisa L.</creator><creator>Karsov, Dmitri</creator><creator>Vena, Richard</creator><creator>Friedman, Hylar L.</creator><creator>Shader, Richard I.</creator><general>Blackwell Publishing Ltd</general><general>Sage Science</general><scope>BSCLL</scope><scope>IQODW</scope><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>199703</creationdate><title>Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P-450 2C9 and Metabolic Inhibitors</title><author>Schmider, Jürgen ; Greenblatt, David J. ; von Moltke, Lisa L. ; Karsov, Dmitri ; Vena, Richard ; Friedman, Hylar L. ; Shader, Richard I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5041-ebd2bd112b863256712e6d70bbd913d2916df7677943323d7d9871d5f64fe1ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Adult</topic><topic>Antifungal Agents - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Cells, Cultured</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - physiology</topic><topic>Estradiol Congeners - metabolism</topic><topic>Estradiol Congeners - pharmacokinetics</topic><topic>Ethinyl Estradiol - metabolism</topic><topic>Female</topic><topic>Fluconazole - pharmacokinetics</topic><topic>Genital system. Reproduction</topic><topic>Humans</topic><topic>Itraconazole - pharmacokinetics</topic><topic>Ketoconazole - pharmacokinetics</topic><topic>Medical sciences</topic><topic>Mestranol - metabolism</topic><topic>Mestranol - pharmacokinetics</topic><topic>Microsomes, Liver - enzymology</topic><topic>Microsomes, Liver - physiology</topic><topic>Pharmacology. Drug treatments</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schmider, Jürgen</creatorcontrib><creatorcontrib>Greenblatt, David J.</creatorcontrib><creatorcontrib>von Moltke, Lisa L.</creatorcontrib><creatorcontrib>Karsov, Dmitri</creatorcontrib><creatorcontrib>Vena, Richard</creatorcontrib><creatorcontrib>Friedman, Hylar L.</creatorcontrib><creatorcontrib>Shader, Richard I.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><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>Journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schmider, Jürgen</au><au>Greenblatt, David J.</au><au>von Moltke, Lisa L.</au><au>Karsov, Dmitri</au><au>Vena, Richard</au><au>Friedman, Hylar L.</au><au>Shader, Richard I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P-450 2C9 and Metabolic Inhibitors</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>J Clin Pharmacol</addtitle><date>1997-03</date><risdate>1997</risdate><volume>37</volume><issue>3</issue><spage>193</spage><epage>200</epage><pages>193-200</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><coden>JCPCBR</coden><abstract>Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17α‐ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 μmol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 μmol/L (range, 1.8–8.3 μmol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60–91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. α‐Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations <2 μmol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (<20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 μmol/L (range, 0.7–3.2 μmol/L) and an average Emax of 90% (range, 77–100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 μmol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>9089421</pmid><doi>10.1002/j.1552-4604.1997.tb04781.x</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0091-2700 |
| ispartof | Journal of clinical pharmacology, 1997-03, Vol.37 (3), p.193-200 |
| issn | 0091-2700 1552-4604 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_78917152 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adult Antifungal Agents - pharmacokinetics Biological and medical sciences Biotransformation Cells, Cultured Chromatography, High Pressure Liquid Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - physiology Estradiol Congeners - metabolism Estradiol Congeners - pharmacokinetics Ethinyl Estradiol - metabolism Female Fluconazole - pharmacokinetics Genital system. Reproduction Humans Itraconazole - pharmacokinetics Ketoconazole - pharmacokinetics Medical sciences Mestranol - metabolism Mestranol - pharmacokinetics Microsomes, Liver - enzymology Microsomes, Liver - physiology Pharmacology. Drug treatments |
| title | Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P-450 2C9 and Metabolic Inhibitors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T05%3A59%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Biotransformation%20of%20Mestranol%20to%20Ethinyl%20Estradiol%20In%20Vitro:%20The%20Role%20of%20Cytochrome%20P-450%202C9%20and%20Metabolic%20Inhibitors&rft.jtitle=Journal%20of%20clinical%20pharmacology&rft.au=Schmider,%20J%C3%BCrgen&rft.date=1997-03&rft.volume=37&rft.issue=3&rft.spage=193&rft.epage=200&rft.pages=193-200&rft.issn=0091-2700&rft.eissn=1552-4604&rft.coden=JCPCBR&rft_id=info:doi/10.1002/j.1552-4604.1997.tb04781.x&rft_dat=%3Cproquest_cross%3E78917152%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=78917152&rft_id=info:pmid/9089421&rfr_iscdi=true |