Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates
Background: Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug. Methods: The drugs were radiola...
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| Veröffentlicht in: | The international journal of neuropsychopharmacology 2015-09, Vol.18 (10), p.pyv036-pyv036 |
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| container_title | The international journal of neuropsychopharmacology |
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| creator | Schou, Magnus Varnäs, Katarina Lundquist, Stefan Nakao, Ryuji Amini, Nahid Takano, Akihiro Finnema, Sjoerd J. Halldin, Christer Farde, Lars |
| description | Background:
Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug.
Methods:
The drugs were radiolabeled with 11C (t
1/2
= 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K
P) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (V
T). Unbound K
P (K
P u,u) was obtained by correction for the free fraction in brain and plasma.
Results:
After intravenous injection, the maximum radioactivity concentration (C
max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C
max, %ID was >2%, indicating a preferential distribution to brain. A lower C
max, %ID was observed for morphine, sulpiride, and verapamil. K
P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K
P u,u close to unity. For morphine, sulpiride, and verapamil, K
P u,u was |
| doi_str_mv | 10.1093/ijnp/pyv036 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_514702</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/ijnp/pyv036</oup_id><sourcerecordid>1709396444</sourcerecordid><originalsourceid>FETCH-LOGICAL-c549t-ca5fb2835a4eca23b3f01a60e57865ffc87ab0be739faa125f20d0ce9333ca063</originalsourceid><addsrcrecordid>eNqNkctvEzEQhy0EoqVw4o58QkhoqZ_74FAJQnhIUalo4cDFmnXG6ZbEXuzdQv57HDZU9IK42CPPNz_b-gh5zNkLzhp53F35_rjfXjNZ3iGHXJVNoTnnd3_XvOBKVwfkQUpXjAmlZXmfHAhdc8l4dUi-LiCukH6B2MHQBU87T19HyOv8Zx_SGJEGRz-hw4jeIp2dntM3cVyllxTo2fyCng_jcrubOg3-ctyAp2ex28CA6SG552Cd8NF-PyKf384vZu-Lxcd3H2avFoXVqhkKC9q1opYaFFoQspWOcSgZ6qoutXO2rqBlLVaycQBcaCfYkllspJQWWCmPSDHlph_Yj63pd_fHrQnQmf3Rt1yh0VxVTGT-ZOJzZ4NLi36IsL41drvju0uzCtdGlarmusoBz_YBMXwfMQ1m0yWL6zV4DGMyvJK64Y0Q_4Nmg02plMro8wm1MaQU0d28iDOzE212os0kOtNP_v7EDfvHbAaeTkAY-38m_QKXAbNW</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1709396444</pqid></control><display><type>article</type><title>Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates</title><source>Oxford Journals Open Access Collection</source><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>SWEPUB Freely available online</source><creator>Schou, Magnus ; Varnäs, Katarina ; Lundquist, Stefan ; Nakao, Ryuji ; Amini, Nahid ; Takano, Akihiro ; Finnema, Sjoerd J. ; Halldin, Christer ; Farde, Lars</creator><creatorcontrib>Schou, Magnus ; Varnäs, Katarina ; Lundquist, Stefan ; Nakao, Ryuji ; Amini, Nahid ; Takano, Akihiro ; Finnema, Sjoerd J. ; Halldin, Christer ; Farde, Lars</creatorcontrib><description>Background:
Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug.
Methods:
The drugs were radiolabeled with 11C (t
1/2
= 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K
P) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (V
T). Unbound K
P (K
P u,u) was obtained by correction for the free fraction in brain and plasma.
Results:
After intravenous injection, the maximum radioactivity concentration (C
max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C
max, %ID was >2%, indicating a preferential distribution to brain. A lower C
max, %ID was observed for morphine, sulpiride, and verapamil. K
P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K
P u,u close to unity. For morphine, sulpiride, and verapamil, K
P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs.
Conclusions:
This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.</description><identifier>ISSN: 1461-1457</identifier><identifier>EISSN: 1469-5111</identifier><identifier>DOI: 10.1093/ijnp/pyv036</identifier><identifier>PMID: 25813017</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Animals ; Brain - diagnostic imaging ; Brain - drug effects ; Brain - metabolism ; Carbon Radioisotopes ; Central Nervous System Agents - administration & dosage ; Central Nervous System Agents - pharmacokinetics ; Cynomolgus ; Dose-Response Relationship, Drug ; Female ; Macaca fascicularis ; Macaca mulatta ; Models, Biological ; Models, Chemical ; Morphine - administration & dosage ; Morphine - pharmacokinetics ; Positron-Emission Tomography ; Radiopharmaceuticals ; Sulpiride - administration & dosage ; Sulpiride - pharmacokinetics ; Verapamil - administration & dosage ; Verapamil - pharmacokinetics</subject><ispartof>The international journal of neuropsychopharmacology, 2015-09, Vol.18 (10), p.pyv036-pyv036</ispartof><rights>The Author 2015. Published by Oxford University Press on behalf of CINP. 2015</rights><rights>The Author 2015. Published by Oxford University Press on behalf of CINP.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c549t-ca5fb2835a4eca23b3f01a60e57865ffc87ab0be739faa125f20d0ce9333ca063</citedby><cites>FETCH-LOGICAL-c549t-ca5fb2835a4eca23b3f01a60e57865ffc87ab0be739faa125f20d0ce9333ca063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648157/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648157/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,1598,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25813017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:132194325$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Schou, Magnus</creatorcontrib><creatorcontrib>Varnäs, Katarina</creatorcontrib><creatorcontrib>Lundquist, Stefan</creatorcontrib><creatorcontrib>Nakao, Ryuji</creatorcontrib><creatorcontrib>Amini, Nahid</creatorcontrib><creatorcontrib>Takano, Akihiro</creatorcontrib><creatorcontrib>Finnema, Sjoerd J.</creatorcontrib><creatorcontrib>Halldin, Christer</creatorcontrib><creatorcontrib>Farde, Lars</creatorcontrib><title>Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates</title><title>The international journal of neuropsychopharmacology</title><addtitle>Int J Neuropsychopharmacol</addtitle><description>Background:
Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug.
Methods:
The drugs were radiolabeled with 11C (t
1/2
= 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K
P) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (V
T). Unbound K
P (K
P u,u) was obtained by correction for the free fraction in brain and plasma.
Results:
After intravenous injection, the maximum radioactivity concentration (C
max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C
max, %ID was >2%, indicating a preferential distribution to brain. A lower C
max, %ID was observed for morphine, sulpiride, and verapamil. K
P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K
P u,u close to unity. For morphine, sulpiride, and verapamil, K
P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs.
Conclusions:
This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.</description><subject>Animals</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Carbon Radioisotopes</subject><subject>Central Nervous System Agents - administration & dosage</subject><subject>Central Nervous System Agents - pharmacokinetics</subject><subject>Cynomolgus</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Macaca fascicularis</subject><subject>Macaca mulatta</subject><subject>Models, Biological</subject><subject>Models, Chemical</subject><subject>Morphine - administration & dosage</subject><subject>Morphine - pharmacokinetics</subject><subject>Positron-Emission Tomography</subject><subject>Radiopharmaceuticals</subject><subject>Sulpiride - administration & dosage</subject><subject>Sulpiride - pharmacokinetics</subject><subject>Verapamil - administration & dosage</subject><subject>Verapamil - pharmacokinetics</subject><issn>1461-1457</issn><issn>1469-5111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqNkctvEzEQhy0EoqVw4o58QkhoqZ_74FAJQnhIUalo4cDFmnXG6ZbEXuzdQv57HDZU9IK42CPPNz_b-gh5zNkLzhp53F35_rjfXjNZ3iGHXJVNoTnnd3_XvOBKVwfkQUpXjAmlZXmfHAhdc8l4dUi-LiCukH6B2MHQBU87T19HyOv8Zx_SGJEGRz-hw4jeIp2dntM3cVyllxTo2fyCng_jcrubOg3-ctyAp2ex28CA6SG552Cd8NF-PyKf384vZu-Lxcd3H2avFoXVqhkKC9q1opYaFFoQspWOcSgZ6qoutXO2rqBlLVaycQBcaCfYkllspJQWWCmPSDHlph_Yj63pd_fHrQnQmf3Rt1yh0VxVTGT-ZOJzZ4NLi36IsL41drvju0uzCtdGlarmusoBz_YBMXwfMQ1m0yWL6zV4DGMyvJK64Y0Q_4Nmg02plMro8wm1MaQU0d28iDOzE212os0kOtNP_v7EDfvHbAaeTkAY-38m_QKXAbNW</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Schou, Magnus</creator><creator>Varnäs, Katarina</creator><creator>Lundquist, Stefan</creator><creator>Nakao, Ryuji</creator><creator>Amini, Nahid</creator><creator>Takano, Akihiro</creator><creator>Finnema, Sjoerd J.</creator><creator>Halldin, Christer</creator><creator>Farde, Lars</creator><general>Oxford University Press</general><scope>TOX</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><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20150901</creationdate><title>Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates</title><author>Schou, Magnus ; Varnäs, Katarina ; Lundquist, Stefan ; Nakao, Ryuji ; Amini, Nahid ; Takano, Akihiro ; Finnema, Sjoerd J. ; Halldin, Christer ; Farde, Lars</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c549t-ca5fb2835a4eca23b3f01a60e57865ffc87ab0be739faa125f20d0ce9333ca063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Brain - diagnostic imaging</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Carbon Radioisotopes</topic><topic>Central Nervous System Agents - administration & dosage</topic><topic>Central Nervous System Agents - pharmacokinetics</topic><topic>Cynomolgus</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Macaca fascicularis</topic><topic>Macaca mulatta</topic><topic>Models, Biological</topic><topic>Models, Chemical</topic><topic>Morphine - administration & dosage</topic><topic>Morphine - pharmacokinetics</topic><topic>Positron-Emission Tomography</topic><topic>Radiopharmaceuticals</topic><topic>Sulpiride - administration & dosage</topic><topic>Sulpiride - pharmacokinetics</topic><topic>Verapamil - administration & dosage</topic><topic>Verapamil - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schou, Magnus</creatorcontrib><creatorcontrib>Varnäs, Katarina</creatorcontrib><creatorcontrib>Lundquist, Stefan</creatorcontrib><creatorcontrib>Nakao, Ryuji</creatorcontrib><creatorcontrib>Amini, Nahid</creatorcontrib><creatorcontrib>Takano, Akihiro</creatorcontrib><creatorcontrib>Finnema, Sjoerd J.</creatorcontrib><creatorcontrib>Halldin, Christer</creatorcontrib><creatorcontrib>Farde, Lars</creatorcontrib><collection>Oxford Journals Open Access Collection</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><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>The international journal of neuropsychopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schou, Magnus</au><au>Varnäs, Katarina</au><au>Lundquist, Stefan</au><au>Nakao, Ryuji</au><au>Amini, Nahid</au><au>Takano, Akihiro</au><au>Finnema, Sjoerd J.</au><au>Halldin, Christer</au><au>Farde, Lars</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates</atitle><jtitle>The international journal of neuropsychopharmacology</jtitle><addtitle>Int J Neuropsychopharmacol</addtitle><date>2015-09-01</date><risdate>2015</risdate><volume>18</volume><issue>10</issue><spage>pyv036</spage><epage>pyv036</epage><pages>pyv036-pyv036</pages><issn>1461-1457</issn><eissn>1469-5111</eissn><abstract>Background:
Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug.
Methods:
The drugs were radiolabeled with 11C (t
1/2
= 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K
P) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (V
T). Unbound K
P (K
P u,u) was obtained by correction for the free fraction in brain and plasma.
Results:
After intravenous injection, the maximum radioactivity concentration (C
max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C
max, %ID was >2%, indicating a preferential distribution to brain. A lower C
max, %ID was observed for morphine, sulpiride, and verapamil. K
P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K
P u,u close to unity. For morphine, sulpiride, and verapamil, K
P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs.
Conclusions:
This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>25813017</pmid><doi>10.1093/ijnp/pyv036</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1461-1457 |
| ispartof | The international journal of neuropsychopharmacology, 2015-09, Vol.18 (10), p.pyv036-pyv036 |
| issn | 1461-1457 1469-5111 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_514702 |
| source | Oxford Journals Open Access Collection; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online |
| subjects | Animals Brain - diagnostic imaging Brain - drug effects Brain - metabolism Carbon Radioisotopes Central Nervous System Agents - administration & dosage Central Nervous System Agents - pharmacokinetics Cynomolgus Dose-Response Relationship, Drug Female Macaca fascicularis Macaca mulatta Models, Biological Models, Chemical Morphine - administration & dosage Morphine - pharmacokinetics Positron-Emission Tomography Radiopharmaceuticals Sulpiride - administration & dosage Sulpiride - pharmacokinetics Verapamil - administration & dosage Verapamil - pharmacokinetics |
| title | Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates |
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