A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions
The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001–3 mg) to 12 healthy participants, stratified according to CY...
Gespeichert in:
| Veröffentlicht in: | Clinical pharmacology and therapeutics 2013-06, Vol.93 (6), p.564-571 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 571 |
|---|---|
| container_issue | 6 |
| container_start_page | 564 |
| container_title | Clinical pharmacology and therapeutics |
| container_volume | 93 |
| creator | Halama, B Hohmann, N Burhenne, J Weiss, J Mikus, G Haefeli, W E |
| description | The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001–3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and Cmax increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000–fold concentration range, and therefore that nano– and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.
Clinical Pharmacology & Therapeutics (2013); 93 6, 564–571. doi:10.1038/clpt.2013.27 |
| doi_str_mv | 10.1038/clpt.2013.27 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1353984945</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1353984945</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4737-2326899fdf4f5ab54709fcfcfb5ffc774d484ab5b148f03d353035216117e0733</originalsourceid><addsrcrecordid>eNp9kM1v1DAQxS1ERbeFG2fkCxKHZvFn7BxXaWkrbctKXUCcLMexSyAbb20HWv56nO5SbmgOoxn93pvRA-A1RnOMqHxv-m2aE4TpnIhnYIY5JUXJKX8OZgihqqgILQ_BUYzf88gqKV-AQ0I5xgLjGVgv4LUe_G3QG3jqo4XewfTNwvrrii7gKvjGwpuxiSnoZOFV1-rfvs9s8vDsp-7HaXsaxlt4OSQbtEmdH-JLcOB0H-2rfT8Gnz6creuLYvnx_LJeLAvDBBUFoaSUVeVaxxzXDWcCVc7karhzRgjWMsnyvsFMOkRbyiminOAy_26RoPQYvNv5boO_G21MatNFY_teD9aPUeGsqCSrGM_oyQ41wccYrFPb0G10eFAYqSlHNeWophwVERl_s3cem41tn-C_wWXg7R7Q0ejeBT2YLv7jBMsuYrordtyvrrcP_z2q6tW6Xq7W0_j4QrFTdjHZ-yelDj9UOVmrL9fnSnCJb67oZyXpH3-EmV8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1353984945</pqid></control><display><type>article</type><title>A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions</title><source>MEDLINE</source><source>Wiley Journals</source><creator>Halama, B ; Hohmann, N ; Burhenne, J ; Weiss, J ; Mikus, G ; Haefeli, W E</creator><creatorcontrib>Halama, B ; Hohmann, N ; Burhenne, J ; Weiss, J ; Mikus, G ; Haefeli, W E</creatorcontrib><description>The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001–3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and Cmax increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000–fold concentration range, and therefore that nano– and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.
Clinical Pharmacology & Therapeutics (2013); 93 6, 564–571. doi:10.1038/clpt.2013.27</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1038/clpt.2013.27</identifier><identifier>PMID: 23511711</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>Basingstoke: Blackwell Publishing Ltd</publisher><subject>Adolescent ; Adult ; Alleles ; Area Under Curve ; Biological and medical sciences ; Cytochrome P-450 CYP3A - genetics ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P-450 CYP3A Inhibitors ; Dose-Response Relationship, Drug ; Drug Interactions - genetics ; Female ; Genotype ; Humans ; Ketoconazole - administration & dosage ; Ketoconazole - pharmacology ; Male ; Medical sciences ; Midazolam - administration & dosage ; Midazolam - pharmacokinetics ; Midazolam - pharmacology ; Middle Aged ; Pharmacology. Drug treatments ; Sex Characteristics</subject><ispartof>Clinical pharmacology and therapeutics, 2013-06, Vol.93 (6), p.564-571</ispartof><rights>2013 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4737-2326899fdf4f5ab54709fcfcfb5ffc774d484ab5b148f03d353035216117e0733</citedby><cites>FETCH-LOGICAL-c4737-2326899fdf4f5ab54709fcfcfb5ffc774d484ab5b148f03d353035216117e0733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1038%2Fclpt.2013.27$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1038%2Fclpt.2013.27$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27427375$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23511711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Halama, B</creatorcontrib><creatorcontrib>Hohmann, N</creatorcontrib><creatorcontrib>Burhenne, J</creatorcontrib><creatorcontrib>Weiss, J</creatorcontrib><creatorcontrib>Mikus, G</creatorcontrib><creatorcontrib>Haefeli, W E</creatorcontrib><title>A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clinical Pharmacology & Therapeutics</addtitle><description>The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001–3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and Cmax increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000–fold concentration range, and therefore that nano– and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.
Clinical Pharmacology & Therapeutics (2013); 93 6, 564–571. doi:10.1038/clpt.2013.27</description><subject>Adolescent</subject><subject>Adult</subject><subject>Alleles</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 CYP3A - genetics</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Cytochrome P-450 CYP3A Inhibitors</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Interactions - genetics</subject><subject>Female</subject><subject>Genotype</subject><subject>Humans</subject><subject>Ketoconazole - administration & dosage</subject><subject>Ketoconazole - pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Midazolam - administration & dosage</subject><subject>Midazolam - pharmacokinetics</subject><subject>Midazolam - pharmacology</subject><subject>Middle Aged</subject><subject>Pharmacology. Drug treatments</subject><subject>Sex Characteristics</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1v1DAQxS1ERbeFG2fkCxKHZvFn7BxXaWkrbctKXUCcLMexSyAbb20HWv56nO5SbmgOoxn93pvRA-A1RnOMqHxv-m2aE4TpnIhnYIY5JUXJKX8OZgihqqgILQ_BUYzf88gqKV-AQ0I5xgLjGVgv4LUe_G3QG3jqo4XewfTNwvrrii7gKvjGwpuxiSnoZOFV1-rfvs9s8vDsp-7HaXsaxlt4OSQbtEmdH-JLcOB0H-2rfT8Gnz6creuLYvnx_LJeLAvDBBUFoaSUVeVaxxzXDWcCVc7karhzRgjWMsnyvsFMOkRbyiminOAy_26RoPQYvNv5boO_G21MatNFY_teD9aPUeGsqCSrGM_oyQ41wccYrFPb0G10eFAYqSlHNeWophwVERl_s3cem41tn-C_wWXg7R7Q0ejeBT2YLv7jBMsuYrordtyvrrcP_z2q6tW6Xq7W0_j4QrFTdjHZ-yelDj9UOVmrL9fnSnCJb67oZyXpH3-EmV8</recordid><startdate>201306</startdate><enddate>201306</enddate><creator>Halama, B</creator><creator>Hohmann, N</creator><creator>Burhenne, J</creator><creator>Weiss, J</creator><creator>Mikus, G</creator><creator>Haefeli, W E</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing Group</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>201306</creationdate><title>A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions</title><author>Halama, B ; Hohmann, N ; Burhenne, J ; Weiss, J ; Mikus, G ; Haefeli, W E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4737-2326899fdf4f5ab54709fcfcfb5ffc774d484ab5b148f03d353035216117e0733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Alleles</topic><topic>Area Under Curve</topic><topic>Biological and medical sciences</topic><topic>Cytochrome P-450 CYP3A - genetics</topic><topic>Cytochrome P-450 CYP3A - metabolism</topic><topic>Cytochrome P-450 CYP3A Inhibitors</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Interactions - genetics</topic><topic>Female</topic><topic>Genotype</topic><topic>Humans</topic><topic>Ketoconazole - administration & dosage</topic><topic>Ketoconazole - pharmacology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Midazolam - administration & dosage</topic><topic>Midazolam - pharmacokinetics</topic><topic>Midazolam - pharmacology</topic><topic>Middle Aged</topic><topic>Pharmacology. Drug treatments</topic><topic>Sex Characteristics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Halama, B</creatorcontrib><creatorcontrib>Hohmann, N</creatorcontrib><creatorcontrib>Burhenne, J</creatorcontrib><creatorcontrib>Weiss, J</creatorcontrib><creatorcontrib>Mikus, G</creatorcontrib><creatorcontrib>Haefeli, W E</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>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Halama, B</au><au>Hohmann, N</au><au>Burhenne, J</au><au>Weiss, J</au><au>Mikus, G</au><au>Haefeli, W E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clinical Pharmacology & Therapeutics</addtitle><date>2013-06</date><risdate>2013</risdate><volume>93</volume><issue>6</issue><spage>564</spage><epage>571</epage><pages>564-571</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001–3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and Cmax increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000–fold concentration range, and therefore that nano– and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.
Clinical Pharmacology & Therapeutics (2013); 93 6, 564–571. doi:10.1038/clpt.2013.27</abstract><cop>Basingstoke</cop><pub>Blackwell Publishing Ltd</pub><pmid>23511711</pmid><doi>10.1038/clpt.2013.27</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-9236 |
| ispartof | Clinical pharmacology and therapeutics, 2013-06, Vol.93 (6), p.564-571 |
| issn | 0009-9236 1532-6535 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1353984945 |
| source | MEDLINE; Wiley Journals |
| subjects | Adolescent Adult Alleles Area Under Curve Biological and medical sciences Cytochrome P-450 CYP3A - genetics Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 CYP3A Inhibitors Dose-Response Relationship, Drug Drug Interactions - genetics Female Genotype Humans Ketoconazole - administration & dosage Ketoconazole - pharmacology Male Medical sciences Midazolam - administration & dosage Midazolam - pharmacokinetics Midazolam - pharmacology Middle Aged Pharmacology. Drug treatments Sex Characteristics |
| title | A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T01%3A01%3A26IST&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=A%20Nanogram%20Dose%20of%20the%20CYP3A%20Probe%20Substrate%20Midazolam%20to%20Evaluate%20Drug%20Interactions&rft.jtitle=Clinical%20pharmacology%20and%20therapeutics&rft.au=Halama,%20B&rft.date=2013-06&rft.volume=93&rft.issue=6&rft.spage=564&rft.epage=571&rft.pages=564-571&rft.issn=0009-9236&rft.eissn=1532-6535&rft.coden=CLPTAT&rft_id=info:doi/10.1038/clpt.2013.27&rft_dat=%3Cproquest_cross%3E1353984945%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=1353984945&rft_id=info:pmid/23511711&rfr_iscdi=true |