Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age
The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open‐label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years...
Gespeichert in:
| Veröffentlicht in: | Clinical pharmacology and therapeutics 2011-11, Vol.90 (5), p.693-700 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 700 |
|---|---|
| container_issue | 5 |
| container_start_page | 693 |
| container_title | Clinical pharmacology and therapeutics |
| container_volume | 90 |
| creator | Desta, Z Kreutz, Y Nguyen, A T Li, L Skaar, T Kamdem, L K Henry, N L Hayes, D F Storniolo, A M Stearns, V Hoffmann, E Tyndale, R F Flockhart, D A |
| description | The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open‐label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10‐fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.
Clinical Pharmacology & Therapeutics (2011); 90 5, 693–700. doi:10.1038/clpt.2011.174 |
| doi_str_mv | 10.1038/clpt.2011.174 |
| format | Article |
| fullrecord | <record><control><sourceid>wiley_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3667657</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>CPTCLPT2011174</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4664-635a0319d22cb630fda177663d2ac2c87792f64eb74023f6a95beec5902098903</originalsourceid><addsrcrecordid>eNp9kU9v1DAQxS0EokvhyBX5wq1Z_Cex4wtSGkGptIgcFipO1qzjtEZZe2W7wPIp-MgkSilw4TR6mt-8Gfsh9JySNSW8fmXGQ14zQumayvIBWtGKs0JUvHqIVoQQVSjGxQl6ktKXSZaqrh-jE0aVnBCyQj-7EdIe8MbmGH6E0eI2eGN9jpBd8Ak7j7uQ8t76cIDbBCO-CpPAVy7f4PNoIWXcwjQScRMtblIKxkG2_UK0nzvWCHxhvc3O4E8QHficzvB56I_4PaSEL31vv59h8D1uru1T9GiAMdlnd_UUfXz7Ztu-KzYfLi7bZlOYUoiyELwCwqnqGTM7wcnQA5VSCN4zMMzUUio2iNLuZEkYHwSoametqRRhRNWK8FP0evE93O72tl-ePOpDdHuIRx3A6X873t3o6_BVcyGkqORkUCwGJoaUoh3uZynRczR6jkbP0egpmol_8ffCe_p3FhPw8g6AZGAc4vSrLv3hSklrRWcjtXDf3GiP_9-q227bbrrtrOcjfgFTn6ou</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age</title><source>MEDLINE</source><source>Wiley Online Library Journals</source><creator>Desta, Z ; Kreutz, Y ; Nguyen, A T ; Li, L ; Skaar, T ; Kamdem, L K ; Henry, N L ; Hayes, D F ; Storniolo, A M ; Stearns, V ; Hoffmann, E ; Tyndale, R F ; Flockhart, D A</creator><creatorcontrib>Desta, Z ; Kreutz, Y ; Nguyen, A T ; Li, L ; Skaar, T ; Kamdem, L K ; Henry, N L ; Hayes, D F ; Storniolo, A M ; Stearns, V ; Hoffmann, E ; Tyndale, R F ; Flockhart, D A</creatorcontrib><description>The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open‐label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10‐fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.
Clinical Pharmacology & Therapeutics (2011); 90 5, 693–700. doi:10.1038/clpt.2011.174</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1038/clpt.2011.174</identifier><identifier>PMID: 21975350</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing Group</publisher><subject>Administration, Oral ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Androstadienes - therapeutic use ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Aryl Hydrocarbon Hydroxylases - genetics ; Biological and medical sciences ; Body Mass Index ; Breast Neoplasms - drug therapy ; Cross-Over Studies ; Cytochrome P-450 CYP2A6 ; Cytochrome P-450 CYP3A - genetics ; Female ; Genetic Variation ; Genotype ; Gynecology. Andrology. Obstetrics ; Humans ; Mammary gland diseases ; Medical sciences ; Middle Aged ; Nitriles - pharmacokinetics ; Nitriles - therapeutic use ; Pharmacogenetics ; Pharmacology. Drug treatments ; Postmenopause ; Prospective Studies ; Triazoles - pharmacokinetics ; Triazoles - therapeutic use ; Tumors</subject><ispartof>Clinical pharmacology and therapeutics, 2011-11, Vol.90 (5), p.693-700</ispartof><rights>2011 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2015 INIST-CNRS</rights><rights>2011 American Society for Clinical Pharmacology and Therapeutics 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4664-635a0319d22cb630fda177663d2ac2c87792f64eb74023f6a95beec5902098903</citedby><cites>FETCH-LOGICAL-c4664-635a0319d22cb630fda177663d2ac2c87792f64eb74023f6a95beec5902098903</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.2011.174$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1038%2Fclpt.2011.174$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24718914$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21975350$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Desta, Z</creatorcontrib><creatorcontrib>Kreutz, Y</creatorcontrib><creatorcontrib>Nguyen, A T</creatorcontrib><creatorcontrib>Li, L</creatorcontrib><creatorcontrib>Skaar, T</creatorcontrib><creatorcontrib>Kamdem, L K</creatorcontrib><creatorcontrib>Henry, N L</creatorcontrib><creatorcontrib>Hayes, D F</creatorcontrib><creatorcontrib>Storniolo, A M</creatorcontrib><creatorcontrib>Stearns, V</creatorcontrib><creatorcontrib>Hoffmann, E</creatorcontrib><creatorcontrib>Tyndale, R F</creatorcontrib><creatorcontrib>Flockhart, D A</creatorcontrib><title>Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open‐label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10‐fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.
Clinical Pharmacology & Therapeutics (2011); 90 5, 693–700. doi:10.1038/clpt.2011.174</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Age Factors</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Androstadienes - therapeutic use</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Aryl Hydrocarbon Hydroxylases - genetics</subject><subject>Biological and medical sciences</subject><subject>Body Mass Index</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Cross-Over Studies</subject><subject>Cytochrome P-450 CYP2A6</subject><subject>Cytochrome P-450 CYP3A - genetics</subject><subject>Female</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Nitriles - pharmacokinetics</subject><subject>Nitriles - therapeutic use</subject><subject>Pharmacogenetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Postmenopause</subject><subject>Prospective Studies</subject><subject>Triazoles - pharmacokinetics</subject><subject>Triazoles - therapeutic use</subject><subject>Tumors</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxS0EokvhyBX5wq1Z_Cex4wtSGkGptIgcFipO1qzjtEZZe2W7wPIp-MgkSilw4TR6mt-8Gfsh9JySNSW8fmXGQ14zQumayvIBWtGKs0JUvHqIVoQQVSjGxQl6ktKXSZaqrh-jE0aVnBCyQj-7EdIe8MbmGH6E0eI2eGN9jpBd8Ak7j7uQ8t76cIDbBCO-CpPAVy7f4PNoIWXcwjQScRMtblIKxkG2_UK0nzvWCHxhvc3O4E8QHficzvB56I_4PaSEL31vv59h8D1uru1T9GiAMdlnd_UUfXz7Ztu-KzYfLi7bZlOYUoiyELwCwqnqGTM7wcnQA5VSCN4zMMzUUio2iNLuZEkYHwSoametqRRhRNWK8FP0evE93O72tl-ePOpDdHuIRx3A6X873t3o6_BVcyGkqORkUCwGJoaUoh3uZynRczR6jkbP0egpmol_8ffCe_p3FhPw8g6AZGAc4vSrLv3hSklrRWcjtXDf3GiP_9-q227bbrrtrOcjfgFTn6ou</recordid><startdate>201111</startdate><enddate>201111</enddate><creator>Desta, Z</creator><creator>Kreutz, Y</creator><creator>Nguyen, A T</creator><creator>Li, L</creator><creator>Skaar, T</creator><creator>Kamdem, L K</creator><creator>Henry, N L</creator><creator>Hayes, D F</creator><creator>Storniolo, A M</creator><creator>Stearns, V</creator><creator>Hoffmann, E</creator><creator>Tyndale, R F</creator><creator>Flockhart, D A</creator><general>Nature Publishing Group</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>5PM</scope></search><sort><creationdate>201111</creationdate><title>Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age</title><author>Desta, Z ; Kreutz, Y ; Nguyen, A T ; Li, L ; Skaar, T ; Kamdem, L K ; Henry, N L ; Hayes, D F ; Storniolo, A M ; Stearns, V ; Hoffmann, E ; Tyndale, R F ; Flockhart, D A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4664-635a0319d22cb630fda177663d2ac2c87792f64eb74023f6a95beec5902098903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Age Factors</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Androstadienes - therapeutic use</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Aryl Hydrocarbon Hydroxylases - genetics</topic><topic>Biological and medical sciences</topic><topic>Body Mass Index</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Cross-Over Studies</topic><topic>Cytochrome P-450 CYP2A6</topic><topic>Cytochrome P-450 CYP3A - genetics</topic><topic>Female</topic><topic>Genetic Variation</topic><topic>Genotype</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Nitriles - pharmacokinetics</topic><topic>Nitriles - therapeutic use</topic><topic>Pharmacogenetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Postmenopause</topic><topic>Prospective Studies</topic><topic>Triazoles - pharmacokinetics</topic><topic>Triazoles - therapeutic use</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Desta, Z</creatorcontrib><creatorcontrib>Kreutz, Y</creatorcontrib><creatorcontrib>Nguyen, A T</creatorcontrib><creatorcontrib>Li, L</creatorcontrib><creatorcontrib>Skaar, T</creatorcontrib><creatorcontrib>Kamdem, L K</creatorcontrib><creatorcontrib>Henry, N L</creatorcontrib><creatorcontrib>Hayes, D F</creatorcontrib><creatorcontrib>Storniolo, A M</creatorcontrib><creatorcontrib>Stearns, V</creatorcontrib><creatorcontrib>Hoffmann, E</creatorcontrib><creatorcontrib>Tyndale, R F</creatorcontrib><creatorcontrib>Flockhart, D A</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>PubMed Central (Full Participant titles)</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Desta, Z</au><au>Kreutz, Y</au><au>Nguyen, A T</au><au>Li, L</au><au>Skaar, T</au><au>Kamdem, L K</au><au>Henry, N L</au><au>Hayes, D F</au><au>Storniolo, A M</au><au>Stearns, V</au><au>Hoffmann, E</au><au>Tyndale, R F</au><au>Flockhart, D A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2011-11</date><risdate>2011</risdate><volume>90</volume><issue>5</issue><spage>693</spage><epage>700</epage><pages>693-700</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open‐label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10‐fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.
Clinical Pharmacology & Therapeutics (2011); 90 5, 693–700. doi:10.1038/clpt.2011.174</abstract><cop>Basingstoke</cop><pub>Nature Publishing Group</pub><pmid>21975350</pmid><doi>10.1038/clpt.2011.174</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-9236 |
| ispartof | Clinical pharmacology and therapeutics, 2011-11, Vol.90 (5), p.693-700 |
| issn | 0009-9236 1532-6535 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3667657 |
| source | MEDLINE; Wiley Online Library Journals |
| subjects | Administration, Oral Adult Age Factors Aged Aged, 80 and over Androstadienes - therapeutic use Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Aryl Hydrocarbon Hydroxylases - genetics Biological and medical sciences Body Mass Index Breast Neoplasms - drug therapy Cross-Over Studies Cytochrome P-450 CYP2A6 Cytochrome P-450 CYP3A - genetics Female Genetic Variation Genotype Gynecology. Andrology. Obstetrics Humans Mammary gland diseases Medical sciences Middle Aged Nitriles - pharmacokinetics Nitriles - therapeutic use Pharmacogenetics Pharmacology. Drug treatments Postmenopause Prospective Studies Triazoles - pharmacokinetics Triazoles - therapeutic use Tumors |
| title | Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T20%3A50%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-wiley_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Plasma%20Letrozole%20Concentrations%20in%20Postmenopausal%20Women%20With%20Breast%20Cancer%20Are%20Associated%20With%20CYP2A6%20Genetic%20Variants,%20Body%20Mass%20Index,%20and%20Age&rft.jtitle=Clinical%20pharmacology%20and%20therapeutics&rft.au=Desta,%20Z&rft.date=2011-11&rft.volume=90&rft.issue=5&rft.spage=693&rft.epage=700&rft.pages=693-700&rft.issn=0009-9236&rft.eissn=1532-6535&rft.coden=CLPTAT&rft_id=info:doi/10.1038/clpt.2011.174&rft_dat=%3Cwiley_pubme%3ECPTCLPT2011174%3C/wiley_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/21975350&rfr_iscdi=true |