Urinary excretion of 6β‐hydroxycortisol as an in vivo marker for CYP3A induction: Applications and recommendations
Objective To evaluate the usefulness of 6β‐hydroxycortisol as a screen for CYP3A induction in early‐phase drug development. Methods Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 4...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 1998-06, Vol.63 (6), p.617-622 |
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| creator | Kovacs, Steven J. Martin, David E. Everitt, Daniel E. Patterson, Scott D. Jorkasky, Diane K. |
| description | Objective
To evaluate the usefulness of 6β‐hydroxycortisol as a screen for CYP3A induction in early‐phase drug development.
Methods
Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24‐hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6β‐hydroxycortisol and 17‐hydroxycorticosteroid concentrations.
Results
Subjects in the rifampin group had a significant increase from predose value in the 24‐hour urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to 17‐hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6β‐hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter.
Conclusions
Urinary excretion of 6β‐hydroxycortisol may be useful as a screening tool in early‐phase development to assess the potential for an investigational drug to induce CYP3A.
Clinical Pharmacology & Therapeutics (1998) 63, 617–622; doi: |
| doi_str_mv | 10.1016/S0009-9236(98)90084-4 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_79999406</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>79999406</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3900-3dbeaac75732c8a15a7fe4d1c2e8b8cd49a23a67a79dbb34f32c32638cb269d63</originalsourceid><addsrcrecordid>eNqNkE1u2zAQhYmgQer8HCEAF0XRLpTyR6LIrmIITRvAQAzEWWRFUCSFsJVEl7TSaJcj5Cw9SA_Rk5SKDa_LDTHzvjeDeQCcY3SBEWafbhFCIhOEsg-CfxQI8TzLD8AMF5RkrKDFGzDbI2_BcYzfU5kLzo_AkWCM4rKYgeEuuF6FEdonHezG-R76BrI_v_8-vzyMJvinUfuwcdG3UEWoeuh6-OgePexU-GEDbHyA1f2SzpNgBj1N-Azn63XrtJqKyWNgsNp3ne3NtncKDhvVRnu2-0_A3dWXVfUtW9x8va7mi0zTdFBGTW2V0mVRUqK5woUqG5sbrInlNdcmF4pQxUpVClPXNG8SRgmjXNeECcPoCXi_nbsO_udg40Z2Lmrbtqq3foiyFOnlaAKLLaiDjzHYRq6DSxeOEiM5xS1f45ZTllJw-Rq3zJPvfLdgqDtr9q5dvkl_t9NV1Kptguq1i3uMUEoo4Qm73GK_XGvH_9stq-WqWixXWAjOEP0HabWeSw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>79999406</pqid></control><display><type>article</type><title>Urinary excretion of 6β‐hydroxycortisol as an in vivo marker for CYP3A induction: Applications and recommendations</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Kovacs, Steven J. ; Martin, David E. ; Everitt, Daniel E. ; Patterson, Scott D. ; Jorkasky, Diane K.</creator><creatorcontrib>Kovacs, Steven J. ; Martin, David E. ; Everitt, Daniel E. ; Patterson, Scott D. ; Jorkasky, Diane K.</creatorcontrib><description>Objective
To evaluate the usefulness of 6β‐hydroxycortisol as a screen for CYP3A induction in early‐phase drug development.
Methods
Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24‐hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6β‐hydroxycortisol and 17‐hydroxycorticosteroid concentrations.
Results
Subjects in the rifampin group had a significant increase from predose value in the 24‐hour urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to 17‐hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6β‐hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter.
Conclusions
Urinary excretion of 6β‐hydroxycortisol may be useful as a screening tool in early‐phase development to assess the potential for an investigational drug to induce CYP3A.
Clinical Pharmacology & Therapeutics (1998) 63, 617–622; doi:</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1016/S0009-9236(98)90084-4</identifier><identifier>PMID: 9663175</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>New York, NY: Nature Publishing</publisher><subject>17-Hydroxycorticosteroids - urine ; Adrenergic alpha-Antagonists - administration & dosage ; Adrenergic alpha-Antagonists - metabolism ; Aged ; Aged, 80 and over ; Antibiotics, Antitubercular - administration & dosage ; Antibiotics, Antitubercular - metabolism ; Aryl Hydrocarbon Hydroxylases ; Biological and medical sciences ; Chromones - administration & dosage ; Chromones - metabolism ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System - biosynthesis ; Drug Administration Schedule ; Enzyme Induction ; General pharmacology ; Humans ; Hydrocortisone - analogs & derivatives ; Hydrocortisone - urine ; Male ; Medical sciences ; Oxidoreductases, N-Demethylating - biosynthesis ; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions ; Pharmacology. Drug treatments ; Reference Values ; Rifampin - administration & dosage ; Rifampin - metabolism</subject><ispartof>Clinical pharmacology and therapeutics, 1998-06, Vol.63 (6), p.617-622</ispartof><rights>1998 American Society for Clinical Pharmacology and Therapeutics</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3900-3dbeaac75732c8a15a7fe4d1c2e8b8cd49a23a67a79dbb34f32c32638cb269d63</citedby><cites>FETCH-LOGICAL-c3900-3dbeaac75732c8a15a7fe4d1c2e8b8cd49a23a67a79dbb34f32c32638cb269d63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2FS0009-9236%2898%2990084-4$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1016%2FS0009-9236%2898%2990084-4$$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=2332328$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9663175$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kovacs, Steven J.</creatorcontrib><creatorcontrib>Martin, David E.</creatorcontrib><creatorcontrib>Everitt, Daniel E.</creatorcontrib><creatorcontrib>Patterson, Scott D.</creatorcontrib><creatorcontrib>Jorkasky, Diane K.</creatorcontrib><title>Urinary excretion of 6β‐hydroxycortisol as an in vivo marker for CYP3A induction: Applications and recommendations</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Objective
To evaluate the usefulness of 6β‐hydroxycortisol as a screen for CYP3A induction in early‐phase drug development.
Methods
Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24‐hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6β‐hydroxycortisol and 17‐hydroxycorticosteroid concentrations.
Results
Subjects in the rifampin group had a significant increase from predose value in the 24‐hour urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to 17‐hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6β‐hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter.
Conclusions
Urinary excretion of 6β‐hydroxycortisol may be useful as a screening tool in early‐phase development to assess the potential for an investigational drug to induce CYP3A.
Clinical Pharmacology & Therapeutics (1998) 63, 617–622; doi:</description><subject>17-Hydroxycorticosteroids - urine</subject><subject>Adrenergic alpha-Antagonists - administration & dosage</subject><subject>Adrenergic alpha-Antagonists - metabolism</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antibiotics, Antitubercular - administration & dosage</subject><subject>Antibiotics, Antitubercular - metabolism</subject><subject>Aryl Hydrocarbon Hydroxylases</subject><subject>Biological and medical sciences</subject><subject>Chromones - administration & dosage</subject><subject>Chromones - metabolism</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System - biosynthesis</subject><subject>Drug Administration Schedule</subject><subject>Enzyme Induction</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>Hydrocortisone - analogs & derivatives</subject><subject>Hydrocortisone - urine</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Oxidoreductases, N-Demethylating - biosynthesis</subject><subject>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</subject><subject>Pharmacology. Drug treatments</subject><subject>Reference Values</subject><subject>Rifampin - administration & dosage</subject><subject>Rifampin - metabolism</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkE1u2zAQhYmgQer8HCEAF0XRLpTyR6LIrmIITRvAQAzEWWRFUCSFsJVEl7TSaJcj5Cw9SA_Rk5SKDa_LDTHzvjeDeQCcY3SBEWafbhFCIhOEsg-CfxQI8TzLD8AMF5RkrKDFGzDbI2_BcYzfU5kLzo_AkWCM4rKYgeEuuF6FEdonHezG-R76BrI_v_8-vzyMJvinUfuwcdG3UEWoeuh6-OgePexU-GEDbHyA1f2SzpNgBj1N-Azn63XrtJqKyWNgsNp3ne3NtncKDhvVRnu2-0_A3dWXVfUtW9x8va7mi0zTdFBGTW2V0mVRUqK5woUqG5sbrInlNdcmF4pQxUpVClPXNG8SRgmjXNeECcPoCXi_nbsO_udg40Z2Lmrbtqq3foiyFOnlaAKLLaiDjzHYRq6DSxeOEiM5xS1f45ZTllJw-Rq3zJPvfLdgqDtr9q5dvkl_t9NV1Kptguq1i3uMUEoo4Qm73GK_XGvH_9stq-WqWixXWAjOEP0HabWeSw</recordid><startdate>199806</startdate><enddate>199806</enddate><creator>Kovacs, Steven J.</creator><creator>Martin, David E.</creator><creator>Everitt, Daniel E.</creator><creator>Patterson, Scott D.</creator><creator>Jorkasky, Diane K.</creator><general>Nature Publishing</general><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>199806</creationdate><title>Urinary excretion of 6β‐hydroxycortisol as an in vivo marker for CYP3A induction: Applications and recommendations</title><author>Kovacs, Steven J. ; Martin, David E. ; Everitt, Daniel E. ; Patterson, Scott D. ; Jorkasky, Diane K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3900-3dbeaac75732c8a15a7fe4d1c2e8b8cd49a23a67a79dbb34f32c32638cb269d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>17-Hydroxycorticosteroids - urine</topic><topic>Adrenergic alpha-Antagonists - administration & dosage</topic><topic>Adrenergic alpha-Antagonists - metabolism</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antibiotics, Antitubercular - administration & dosage</topic><topic>Antibiotics, Antitubercular - metabolism</topic><topic>Aryl Hydrocarbon Hydroxylases</topic><topic>Biological and medical sciences</topic><topic>Chromones - administration & dosage</topic><topic>Chromones - metabolism</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme System - biosynthesis</topic><topic>Drug Administration Schedule</topic><topic>Enzyme Induction</topic><topic>General pharmacology</topic><topic>Humans</topic><topic>Hydrocortisone - analogs & derivatives</topic><topic>Hydrocortisone - urine</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Oxidoreductases, N-Demethylating - biosynthesis</topic><topic>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</topic><topic>Pharmacology. Drug treatments</topic><topic>Reference Values</topic><topic>Rifampin - administration & dosage</topic><topic>Rifampin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kovacs, Steven J.</creatorcontrib><creatorcontrib>Martin, David E.</creatorcontrib><creatorcontrib>Everitt, Daniel E.</creatorcontrib><creatorcontrib>Patterson, Scott D.</creatorcontrib><creatorcontrib>Jorkasky, Diane K.</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>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kovacs, Steven J.</au><au>Martin, David E.</au><au>Everitt, Daniel E.</au><au>Patterson, Scott D.</au><au>Jorkasky, Diane K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Urinary excretion of 6β‐hydroxycortisol as an in vivo marker for CYP3A induction: Applications and recommendations</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>1998-06</date><risdate>1998</risdate><volume>63</volume><issue>6</issue><spage>617</spage><epage>622</epage><pages>617-622</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Objective
To evaluate the usefulness of 6β‐hydroxycortisol as a screen for CYP3A induction in early‐phase drug development.
Methods
Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24‐hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6β‐hydroxycortisol and 17‐hydroxycorticosteroid concentrations.
Results
Subjects in the rifampin group had a significant increase from predose value in the 24‐hour urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to 17‐hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6β‐hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter.
Conclusions
Urinary excretion of 6β‐hydroxycortisol may be useful as a screening tool in early‐phase development to assess the potential for an investigational drug to induce CYP3A.
Clinical Pharmacology & Therapeutics (1998) 63, 617–622; doi:</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>9663175</pmid><doi>10.1016/S0009-9236(98)90084-4</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-9236 |
| ispartof | Clinical pharmacology and therapeutics, 1998-06, Vol.63 (6), p.617-622 |
| issn | 0009-9236 1532-6535 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_79999406 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | 17-Hydroxycorticosteroids - urine Adrenergic alpha-Antagonists - administration & dosage Adrenergic alpha-Antagonists - metabolism Aged Aged, 80 and over Antibiotics, Antitubercular - administration & dosage Antibiotics, Antitubercular - metabolism Aryl Hydrocarbon Hydroxylases Biological and medical sciences Chromones - administration & dosage Chromones - metabolism Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - biosynthesis Drug Administration Schedule Enzyme Induction General pharmacology Humans Hydrocortisone - analogs & derivatives Hydrocortisone - urine Male Medical sciences Oxidoreductases, N-Demethylating - biosynthesis Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions Pharmacology. Drug treatments Reference Values Rifampin - administration & dosage Rifampin - metabolism |
| title | Urinary excretion of 6β‐hydroxycortisol as an in vivo marker for CYP3A induction: Applications and recommendations |
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