Mechanism of Drug-Drug Interactions Between Warfarin and Statins

The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of pharmaceutical sciences 2016-06, Vol.105 (6), p.1976-1986
Hauptverfasser: Shaik, Abdul Naveed, Bohnert, Tonika, Williams, David A., Gan, Lawrence L., LeDuc, Barbara W.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1986
container_issue 6
container_start_page 1976
container_title Journal of pharmaceutical sciences
container_volume 105
creator Shaik, Abdul Naveed
Bohnert, Tonika
Williams, David A.
Gan, Lawrence L.
LeDuc, Barbara W.
description The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450–mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography–mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin was found to be a potent inhibitor of formation of 7-hydroxy warfarin. Uptake and efflux drug transporters do not play any role in these DDIs. The results showed that DDIs between warfarin and statins are primarily caused by cytochrome P-450 inhibition.
doi_str_mv 10.1016/j.xphs.2016.03.011
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1792771707</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0022354916004391</els_id><sourcerecordid>1792771707</sourcerecordid><originalsourceid>FETCH-LOGICAL-c422t-ffd493bcda81685cf06d3f4273ae31c7402ea3723658a737cc81d90a788902183</originalsourceid><addsrcrecordid>eNp9kD1PwzAQhi0EoqXwBxhQRpaEs53EicQAlK9KRQyAGC3XuVBXrVNsh49_T6IWRpa7G573le4h5JhCQoHmZ4vkaz33CevuBHgClO6QIc0YxDlQsUuGAIzFPEvLATnwfgEAOWTZPhkwQYF3_JBcPKCeK2v8Kmrq6Nq1b3E_ookN6JQOprE-usLwiWijV-Vq5YyNlK2ip6CCsf6Q7NVq6fFou0fk5fbmeXwfTx_vJuPLaaxTxkJc11Va8pmuVEHzItM15BWvUya4Qk61SIGh4oLxPCuU4ELrglYlKFEUJTBa8BE53fSuXfPeog9yZbzG5VJZbFovqSiZEFSA6FC2QbVrvHdYy7UzK-W-JQXZm5ML2ZuTvTkJXHYmutDJtr-drbD6i_yq6oDzDYDdlx8GnfTaoNVYGYc6yKox__X_AAlafcs</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1792771707</pqid></control><display><type>article</type><title>Mechanism of Drug-Drug Interactions Between Warfarin and Statins</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Shaik, Abdul Naveed ; Bohnert, Tonika ; Williams, David A. ; Gan, Lawrence L. ; LeDuc, Barbara W.</creator><creatorcontrib>Shaik, Abdul Naveed ; Bohnert, Tonika ; Williams, David A. ; Gan, Lawrence L. ; LeDuc, Barbara W.</creatorcontrib><description>The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450–mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography–mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin was found to be a potent inhibitor of formation of 7-hydroxy warfarin. Uptake and efflux drug transporters do not play any role in these DDIs. The results showed that DDIs between warfarin and statins are primarily caused by cytochrome P-450 inhibition.</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1016/j.xphs.2016.03.011</identifier><identifier>PMID: 27103011</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Anticoagulants - metabolism ; Caco-2 Cells ; CYP enzymes ; cytochrome P450 ; Dose-Response Relationship, Drug ; drug interactions ; Drug Interactions - physiology ; enzyme kinetics ; HEK293 Cells ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism ; inhibition ; LC-MS ; organic anion transporters ; organic anion-transporting polypeptide transporters ; P-glycoprotein ; Protein Binding ; Warfarin - metabolism</subject><ispartof>Journal of pharmaceutical sciences, 2016-06, Vol.105 (6), p.1976-1986</ispartof><rights>2016 American Pharmacists Association</rights><rights>Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-ffd493bcda81685cf06d3f4273ae31c7402ea3723658a737cc81d90a788902183</citedby><cites>FETCH-LOGICAL-c422t-ffd493bcda81685cf06d3f4273ae31c7402ea3723658a737cc81d90a788902183</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27103011$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shaik, Abdul Naveed</creatorcontrib><creatorcontrib>Bohnert, Tonika</creatorcontrib><creatorcontrib>Williams, David A.</creatorcontrib><creatorcontrib>Gan, Lawrence L.</creatorcontrib><creatorcontrib>LeDuc, Barbara W.</creatorcontrib><title>Mechanism of Drug-Drug Interactions Between Warfarin and Statins</title><title>Journal of pharmaceutical sciences</title><addtitle>J Pharm Sci</addtitle><description>The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450–mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography–mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin was found to be a potent inhibitor of formation of 7-hydroxy warfarin. Uptake and efflux drug transporters do not play any role in these DDIs. The results showed that DDIs between warfarin and statins are primarily caused by cytochrome P-450 inhibition.</description><subject>Anticoagulants - metabolism</subject><subject>Caco-2 Cells</subject><subject>CYP enzymes</subject><subject>cytochrome P450</subject><subject>Dose-Response Relationship, Drug</subject><subject>drug interactions</subject><subject>Drug Interactions - physiology</subject><subject>enzyme kinetics</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism</subject><subject>inhibition</subject><subject>LC-MS</subject><subject>organic anion transporters</subject><subject>organic anion-transporting polypeptide transporters</subject><subject>P-glycoprotein</subject><subject>Protein Binding</subject><subject>Warfarin - metabolism</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD1PwzAQhi0EoqXwBxhQRpaEs53EicQAlK9KRQyAGC3XuVBXrVNsh49_T6IWRpa7G573le4h5JhCQoHmZ4vkaz33CevuBHgClO6QIc0YxDlQsUuGAIzFPEvLATnwfgEAOWTZPhkwQYF3_JBcPKCeK2v8Kmrq6Nq1b3E_ookN6JQOprE-usLwiWijV-Vq5YyNlK2ip6CCsf6Q7NVq6fFou0fk5fbmeXwfTx_vJuPLaaxTxkJc11Va8pmuVEHzItM15BWvUya4Qk61SIGh4oLxPCuU4ELrglYlKFEUJTBa8BE53fSuXfPeog9yZbzG5VJZbFovqSiZEFSA6FC2QbVrvHdYy7UzK-W-JQXZm5ML2ZuTvTkJXHYmutDJtr-drbD6i_yq6oDzDYDdlx8GnfTaoNVYGYc6yKox__X_AAlafcs</recordid><startdate>201606</startdate><enddate>201606</enddate><creator>Shaik, Abdul Naveed</creator><creator>Bohnert, Tonika</creator><creator>Williams, David A.</creator><creator>Gan, Lawrence L.</creator><creator>LeDuc, Barbara W.</creator><general>Elsevier Inc</general><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>201606</creationdate><title>Mechanism of Drug-Drug Interactions Between Warfarin and Statins</title><author>Shaik, Abdul Naveed ; Bohnert, Tonika ; Williams, David A. ; Gan, Lawrence L. ; LeDuc, Barbara W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-ffd493bcda81685cf06d3f4273ae31c7402ea3723658a737cc81d90a788902183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Anticoagulants - metabolism</topic><topic>Caco-2 Cells</topic><topic>CYP enzymes</topic><topic>cytochrome P450</topic><topic>Dose-Response Relationship, Drug</topic><topic>drug interactions</topic><topic>Drug Interactions - physiology</topic><topic>enzyme kinetics</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism</topic><topic>inhibition</topic><topic>LC-MS</topic><topic>organic anion transporters</topic><topic>organic anion-transporting polypeptide transporters</topic><topic>P-glycoprotein</topic><topic>Protein Binding</topic><topic>Warfarin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shaik, Abdul Naveed</creatorcontrib><creatorcontrib>Bohnert, Tonika</creatorcontrib><creatorcontrib>Williams, David A.</creatorcontrib><creatorcontrib>Gan, Lawrence L.</creatorcontrib><creatorcontrib>LeDuc, Barbara W.</creatorcontrib><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 pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shaik, Abdul Naveed</au><au>Bohnert, Tonika</au><au>Williams, David A.</au><au>Gan, Lawrence L.</au><au>LeDuc, Barbara W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of Drug-Drug Interactions Between Warfarin and Statins</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J Pharm Sci</addtitle><date>2016-06</date><risdate>2016</risdate><volume>105</volume><issue>6</issue><spage>1976</spage><epage>1986</epage><pages>1976-1986</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><abstract>The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450–mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography–mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin was found to be a potent inhibitor of formation of 7-hydroxy warfarin. Uptake and efflux drug transporters do not play any role in these DDIs. The results showed that DDIs between warfarin and statins are primarily caused by cytochrome P-450 inhibition.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27103011</pmid><doi>10.1016/j.xphs.2016.03.011</doi><tpages>11</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0022-3549
ispartof Journal of pharmaceutical sciences, 2016-06, Vol.105 (6), p.1976-1986
issn 0022-3549
1520-6017
language eng
recordid cdi_proquest_miscellaneous_1792771707
source MEDLINE; Alma/SFX Local Collection
subjects Anticoagulants - metabolism
Caco-2 Cells
CYP enzymes
cytochrome P450
Dose-Response Relationship, Drug
drug interactions
Drug Interactions - physiology
enzyme kinetics
HEK293 Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism
inhibition
LC-MS
organic anion transporters
organic anion-transporting polypeptide transporters
P-glycoprotein
Protein Binding
Warfarin - metabolism
title Mechanism of Drug-Drug Interactions Between Warfarin and Statins
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T01%3A45%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=Mechanism%20of%20Drug-Drug%20Interactions%20Between%20Warfarin%20and%20Statins&rft.jtitle=Journal%20of%20pharmaceutical%20sciences&rft.au=Shaik,%20Abdul%20Naveed&rft.date=2016-06&rft.volume=105&rft.issue=6&rft.spage=1976&rft.epage=1986&rft.pages=1976-1986&rft.issn=0022-3549&rft.eissn=1520-6017&rft_id=info:doi/10.1016/j.xphs.2016.03.011&rft_dat=%3Cproquest_cross%3E1792771707%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=1792771707&rft_id=info:pmid/27103011&rft_els_id=S0022354916004391&rfr_iscdi=true