Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations
Summary Objective Given that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly fo...
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| Veröffentlicht in: | Epilepsia (Copenhagen) 2017-07, Vol.58 (7), p.1234-1243 |
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| creator | Patsalos, Philip N. Zugman, Miguel Lake, Charlotte James, Anthony Ratnaraj, Neville Sander, Josemir W. |
| description | Summary
Objective
Given that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide and N‐desmethyl clobazam), using standardized methodology and under set conditions.
Methods
The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.
Results
Gabapentin and pregabalin are non–protein‐bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs ( |
| doi_str_mv | 10.1111/epi.13802 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1903160120</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1903160120</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4262-358b1380e65441101b5f15e038205dde58fd01bcb87da99266db2f0ab9e33bd73</originalsourceid><addsrcrecordid>eNp1kE1rFTEUQENR7LO66B8oWdrFtDfJy0ymu1KqFgoK6nrIx51HykwyTWYo3XXZpeA_7C8xz_d0ZzaBy-Ek9xByzOCMlXOOkz9jQgE_ICsmuaoYq5tXZAXARNVKBYfkbc53ANDUjXhDDrmSa66ArcjzN0zLSKcUZ_SBGh-cDxsae8ol1WH2xT3gNHtLXVo2mRZI0xSX2QekdvDBWz3QjHMZbC7oJbVxnHTyOYatpU-INMTw8vRr_8bL008Tl-AKGCyGOenZx5Dfkde9HjK-399H5MfH6-9Xn6vbL59uri5vK7vmNa-EVGa7KtZyvWYMmJE9kwhCcZDOoVS9K0NrVON02_K6dob3oE2LQhjXiCPyYect37lfMM_d6LPFYdAB45I71oJgNTAOBT3doTbFnBP23ZT8qNNjx6Dbhu9KnO5P-MKe7LWLGdH9I_-WLsD5DngoPR__b-quv97slL8BKHeQVg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1903160120</pqid></control><display><type>article</type><title>Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Wiley Online Library Free Content</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Patsalos, Philip N. ; Zugman, Miguel ; Lake, Charlotte ; James, Anthony ; Ratnaraj, Neville ; Sander, Josemir W.</creator><creatorcontrib>Patsalos, Philip N. ; Zugman, Miguel ; Lake, Charlotte ; James, Anthony ; Ratnaraj, Neville ; Sander, Josemir W.</creatorcontrib><description>Summary
Objective
Given that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide and N‐desmethyl clobazam), using standardized methodology and under set conditions.
Methods
The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.
Results
Gabapentin and pregabalin are non–protein‐bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).
Significance
These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine‐epoxide and N‐desmethyl‐clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.</description><identifier>ISSN: 0013-9580</identifier><identifier>EISSN: 1528-1167</identifier><identifier>DOI: 10.1111/epi.13802</identifier><identifier>PMID: 28542801</identifier><language>eng</language><publisher>United States</publisher><subject>Adult ; Anticonvulsants - pharmacokinetics ; Anticonvulsants - therapeutic use ; Benzodiazepines - pharmacokinetics ; Biological Availability ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - physiology ; Carbamazepine - analogs & derivatives ; Carbamazepine - pharmacokinetics ; Epilepsy - blood ; Epilepsy - drug therapy ; Epilepsy treatment ; Free fraction ; Gas Chromatography-Mass Spectrometry ; Humans ; New antiepileptic drugs ; Protein Binding - physiology ; Retrospective Studies ; Therapeutic drug monitoring ; Ultracentrifugation</subject><ispartof>Epilepsia (Copenhagen), 2017-07, Vol.58 (7), p.1234-1243</ispartof><rights>Wiley Periodicals, Inc. © 2017 International League Against Epilepsy</rights><rights>Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4262-358b1380e65441101b5f15e038205dde58fd01bcb87da99266db2f0ab9e33bd73</citedby><cites>FETCH-LOGICAL-c4262-358b1380e65441101b5f15e038205dde58fd01bcb87da99266db2f0ab9e33bd73</cites><orcidid>0000-0001-6041-9661</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fepi.13802$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fepi.13802$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28542801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Patsalos, Philip N.</creatorcontrib><creatorcontrib>Zugman, Miguel</creatorcontrib><creatorcontrib>Lake, Charlotte</creatorcontrib><creatorcontrib>James, Anthony</creatorcontrib><creatorcontrib>Ratnaraj, Neville</creatorcontrib><creatorcontrib>Sander, Josemir W.</creatorcontrib><title>Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations</title><title>Epilepsia (Copenhagen)</title><addtitle>Epilepsia</addtitle><description>Summary
Objective
Given that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide and N‐desmethyl clobazam), using standardized methodology and under set conditions.
Methods
The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.
Results
Gabapentin and pregabalin are non–protein‐bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).
Significance
These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine‐epoxide and N‐desmethyl‐clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.</description><subject>Adult</subject><subject>Anticonvulsants - pharmacokinetics</subject><subject>Anticonvulsants - therapeutic use</subject><subject>Benzodiazepines - pharmacokinetics</subject><subject>Biological Availability</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood-Brain Barrier - physiology</subject><subject>Carbamazepine - analogs & derivatives</subject><subject>Carbamazepine - pharmacokinetics</subject><subject>Epilepsy - blood</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy treatment</subject><subject>Free fraction</subject><subject>Gas Chromatography-Mass Spectrometry</subject><subject>Humans</subject><subject>New antiepileptic drugs</subject><subject>Protein Binding - physiology</subject><subject>Retrospective Studies</subject><subject>Therapeutic drug monitoring</subject><subject>Ultracentrifugation</subject><issn>0013-9580</issn><issn>1528-1167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1rFTEUQENR7LO66B8oWdrFtDfJy0ymu1KqFgoK6nrIx51HykwyTWYo3XXZpeA_7C8xz_d0ZzaBy-Ek9xByzOCMlXOOkz9jQgE_ICsmuaoYq5tXZAXARNVKBYfkbc53ANDUjXhDDrmSa66ArcjzN0zLSKcUZ_SBGh-cDxsae8ol1WH2xT3gNHtLXVo2mRZI0xSX2QekdvDBWz3QjHMZbC7oJbVxnHTyOYatpU-INMTw8vRr_8bL008Tl-AKGCyGOenZx5Dfkde9HjK-399H5MfH6-9Xn6vbL59uri5vK7vmNa-EVGa7KtZyvWYMmJE9kwhCcZDOoVS9K0NrVON02_K6dob3oE2LQhjXiCPyYect37lfMM_d6LPFYdAB45I71oJgNTAOBT3doTbFnBP23ZT8qNNjx6Dbhu9KnO5P-MKe7LWLGdH9I_-WLsD5DngoPR__b-quv97slL8BKHeQVg</recordid><startdate>201707</startdate><enddate>201707</enddate><creator>Patsalos, Philip N.</creator><creator>Zugman, Miguel</creator><creator>Lake, Charlotte</creator><creator>James, Anthony</creator><creator>Ratnaraj, Neville</creator><creator>Sander, Josemir W.</creator><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><orcidid>https://orcid.org/0000-0001-6041-9661</orcidid></search><sort><creationdate>201707</creationdate><title>Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations</title><author>Patsalos, Philip N. ; Zugman, Miguel ; Lake, Charlotte ; James, Anthony ; Ratnaraj, Neville ; Sander, Josemir W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4262-358b1380e65441101b5f15e038205dde58fd01bcb87da99266db2f0ab9e33bd73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Anticonvulsants - pharmacokinetics</topic><topic>Anticonvulsants - therapeutic use</topic><topic>Benzodiazepines - pharmacokinetics</topic><topic>Biological Availability</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Blood-Brain Barrier - physiology</topic><topic>Carbamazepine - analogs & derivatives</topic><topic>Carbamazepine - pharmacokinetics</topic><topic>Epilepsy - blood</topic><topic>Epilepsy - drug therapy</topic><topic>Epilepsy treatment</topic><topic>Free fraction</topic><topic>Gas Chromatography-Mass Spectrometry</topic><topic>Humans</topic><topic>New antiepileptic drugs</topic><topic>Protein Binding - physiology</topic><topic>Retrospective Studies</topic><topic>Therapeutic drug monitoring</topic><topic>Ultracentrifugation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Patsalos, Philip N.</creatorcontrib><creatorcontrib>Zugman, Miguel</creatorcontrib><creatorcontrib>Lake, Charlotte</creatorcontrib><creatorcontrib>James, Anthony</creatorcontrib><creatorcontrib>Ratnaraj, Neville</creatorcontrib><creatorcontrib>Sander, Josemir 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>Epilepsia (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Patsalos, Philip N.</au><au>Zugman, Miguel</au><au>Lake, Charlotte</au><au>James, Anthony</au><au>Ratnaraj, Neville</au><au>Sander, Josemir W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations</atitle><jtitle>Epilepsia (Copenhagen)</jtitle><addtitle>Epilepsia</addtitle><date>2017-07</date><risdate>2017</risdate><volume>58</volume><issue>7</issue><spage>1234</spage><epage>1243</epage><pages>1234-1243</pages><issn>0013-9580</issn><eissn>1528-1167</eissn><abstract>Summary
Objective
Given that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide and N‐desmethyl clobazam), using standardized methodology and under set conditions.
Methods
The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.
Results
Gabapentin and pregabalin are non–protein‐bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).
Significance
These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine‐epoxide and N‐desmethyl‐clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.</abstract><cop>United States</cop><pmid>28542801</pmid><doi>10.1111/epi.13802</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-6041-9661</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0013-9580 |
| ispartof | Epilepsia (Copenhagen), 2017-07, Vol.58 (7), p.1234-1243 |
| issn | 0013-9580 1528-1167 |
| language | eng |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Wiley Online Library Free Content; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adult Anticonvulsants - pharmacokinetics Anticonvulsants - therapeutic use Benzodiazepines - pharmacokinetics Biological Availability Blood-Brain Barrier - drug effects Blood-Brain Barrier - physiology Carbamazepine - analogs & derivatives Carbamazepine - pharmacokinetics Epilepsy - blood Epilepsy - drug therapy Epilepsy treatment Free fraction Gas Chromatography-Mass Spectrometry Humans New antiepileptic drugs Protein Binding - physiology Retrospective Studies Therapeutic drug monitoring Ultracentrifugation |
| title | Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations |
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