The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study
Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers...
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| Veröffentlicht in: | PloS one 2016-09, Vol.11 (9), p.e0162084-e0162084 |
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| creator | Gemmati, Donato Burini, Francesco Talarico, Anna Fabbri, Matteo Bertocco, Cesare Vigliano, Marco Moratelli, Stefano Cuneo, Antonio Serino, Maria Luisa Avato, Francesco Maria Tisato, Veronica Gaudio, Rosa Maria |
| description | Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3'-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis.
133 OAT patients were recruited and assessed for warfarin/3'-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups.
In the whole OAT group both warfarin and 3'-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3'-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3'-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p |
| doi_str_mv | 10.1371/journal.pone.0162084 |
| format | Article |
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133 OAT patients were recruited and assessed for warfarin/3'-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups.
In the whole OAT group both warfarin and 3'-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3'-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3'-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3'-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3'-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles.
Our results overall suggest that 3'-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0162084</identifier><identifier>PMID: 27606428</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Administration, Oral ; Aged ; Alleles ; Anticoagulants ; Anticoagulants - administration & dosage ; Anticoagulants - therapeutic use ; Biochemistry ; Biology and Life Sciences ; Calibration ; Chromatography ; Chromatography, High Pressure Liquid ; Cohort Studies ; Correlation ; Correlation analysis ; Cytochrome P-450 ; Dosage ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug dosages ; Enantiomers ; Female ; Genetics ; Genotype ; Genotypes ; High performance liquid chromatography ; Homeostasis ; Humans ; International Normalized Ratio ; Laboratories ; Leg ulcers ; Liquid chromatography ; Male ; Mass spectrometry ; Medical research ; Medicine ; Medicine and Health Sciences ; Metabolites ; Middle Aged ; Molecular biology ; Monitoring ; Multivariate Analysis ; Patients ; Pharmacogenetics ; Pharmacogenomics ; Pharmacology ; Physical Sciences ; Polymerase Chain Reaction ; Public health ; Research and Analysis Methods ; Scientific imaging ; Serum levels ; Surgery ; Therapy ; Thrombosis ; Time Factors ; Treatment Outcome ; Warfarin ; Warfarin - administration & dosage ; Warfarin - analogs & derivatives ; Warfarin - blood ; Warfarin - metabolism ; Warfarin - therapeutic use</subject><ispartof>PloS one, 2016-09, Vol.11 (9), p.e0162084-e0162084</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Gemmati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Gemmati et al 2016 Gemmati et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c626t-c2fa313b3a8c20e703d369fcbfeee463517416265a478fab96a894f35157dda43</citedby><cites>FETCH-LOGICAL-c626t-c2fa313b3a8c20e703d369fcbfeee463517416265a478fab96a894f35157dda43</cites><orcidid>0000-0001-6213-6120</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015920/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015920/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27606428$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gemmati, Donato</creatorcontrib><creatorcontrib>Burini, Francesco</creatorcontrib><creatorcontrib>Talarico, Anna</creatorcontrib><creatorcontrib>Fabbri, Matteo</creatorcontrib><creatorcontrib>Bertocco, Cesare</creatorcontrib><creatorcontrib>Vigliano, Marco</creatorcontrib><creatorcontrib>Moratelli, Stefano</creatorcontrib><creatorcontrib>Cuneo, Antonio</creatorcontrib><creatorcontrib>Serino, Maria Luisa</creatorcontrib><creatorcontrib>Avato, Francesco Maria</creatorcontrib><creatorcontrib>Tisato, Veronica</creatorcontrib><creatorcontrib>Gaudio, Rosa Maria</creatorcontrib><title>The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3'-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis.
133 OAT patients were recruited and assessed for warfarin/3'-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups.
In the whole OAT group both warfarin and 3'-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3'-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3'-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3'-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3'-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles.
Our results overall suggest that 3'-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators.</description><subject>Administration, Oral</subject><subject>Aged</subject><subject>Alleles</subject><subject>Anticoagulants</subject><subject>Anticoagulants - administration & dosage</subject><subject>Anticoagulants - therapeutic use</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Calibration</subject><subject>Chromatography</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cohort Studies</subject><subject>Correlation</subject><subject>Correlation analysis</subject><subject>Cytochrome P-450</subject><subject>Dosage</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Schedule</subject><subject>Drug dosages</subject><subject>Enantiomers</subject><subject>Female</subject><subject>Genetics</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>High performance liquid chromatography</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>International Normalized Ratio</subject><subject>Laboratories</subject><subject>Leg ulcers</subject><subject>Liquid chromatography</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolites</subject><subject>Middle Aged</subject><subject>Molecular biology</subject><subject>Monitoring</subject><subject>Multivariate Analysis</subject><subject>Patients</subject><subject>Pharmacogenetics</subject><subject>Pharmacogenomics</subject><subject>Pharmacology</subject><subject>Physical Sciences</subject><subject>Polymerase Chain Reaction</subject><subject>Public health</subject><subject>Research and Analysis Methods</subject><subject>Scientific imaging</subject><subject>Serum levels</subject><subject>Surgery</subject><subject>Therapy</subject><subject>Thrombosis</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>Warfarin</subject><subject>Warfarin - 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administration & dosage</topic><topic>Warfarin - analogs & derivatives</topic><topic>Warfarin - blood</topic><topic>Warfarin - metabolism</topic><topic>Warfarin - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gemmati, Donato</creatorcontrib><creatorcontrib>Burini, Francesco</creatorcontrib><creatorcontrib>Talarico, Anna</creatorcontrib><creatorcontrib>Fabbri, Matteo</creatorcontrib><creatorcontrib>Bertocco, Cesare</creatorcontrib><creatorcontrib>Vigliano, Marco</creatorcontrib><creatorcontrib>Moratelli, Stefano</creatorcontrib><creatorcontrib>Cuneo, Antonio</creatorcontrib><creatorcontrib>Serino, Maria Luisa</creatorcontrib><creatorcontrib>Avato, Francesco Maria</creatorcontrib><creatorcontrib>Tisato, Veronica</creatorcontrib><creatorcontrib>Gaudio, Rosa Maria</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gemmati, Donato</au><au>Burini, Francesco</au><au>Talarico, Anna</au><au>Fabbri, Matteo</au><au>Bertocco, Cesare</au><au>Vigliano, Marco</au><au>Moratelli, Stefano</au><au>Cuneo, Antonio</au><au>Serino, Maria Luisa</au><au>Avato, Francesco Maria</au><au>Tisato, Veronica</au><au>Gaudio, Rosa Maria</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-09-08</date><risdate>2016</risdate><volume>11</volume><issue>9</issue><spage>e0162084</spage><epage>e0162084</epage><pages>e0162084-e0162084</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3'-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis.
133 OAT patients were recruited and assessed for warfarin/3'-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups.
In the whole OAT group both warfarin and 3'-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3'-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3'-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3'-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3'-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles.
Our results overall suggest that 3'-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27606428</pmid><doi>10.1371/journal.pone.0162084</doi><orcidid>https://orcid.org/0000-0001-6213-6120</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-09, Vol.11 (9), p.e0162084-e0162084 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1817860276 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Administration, Oral Aged Alleles Anticoagulants Anticoagulants - administration & dosage Anticoagulants - therapeutic use Biochemistry Biology and Life Sciences Calibration Chromatography Chromatography, High Pressure Liquid Cohort Studies Correlation Correlation analysis Cytochrome P-450 Dosage Dose-Response Relationship, Drug Drug Administration Schedule Drug dosages Enantiomers Female Genetics Genotype Genotypes High performance liquid chromatography Homeostasis Humans International Normalized Ratio Laboratories Leg ulcers Liquid chromatography Male Mass spectrometry Medical research Medicine Medicine and Health Sciences Metabolites Middle Aged Molecular biology Monitoring Multivariate Analysis Patients Pharmacogenetics Pharmacogenomics Pharmacology Physical Sciences Polymerase Chain Reaction Public health Research and Analysis Methods Scientific imaging Serum levels Surgery Therapy Thrombosis Time Factors Treatment Outcome Warfarin Warfarin - administration & dosage Warfarin - analogs & derivatives Warfarin - blood Warfarin - metabolism Warfarin - therapeutic use |
| title | The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study |
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