Distribution of Gacyclidine Enantiomers after Experimental Spinal Cord Injury in Rats: Possible Involvement of an Active Transport System
The pharmacokinetics of gacyclidine enantiomers, a noncompetitive N‐methyl‐d‐aspartate (NMDA) antagonist, were studied in plasma and spinal cord extracellular fluid (ECF) after experimental spinal cord injury in rats. Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal...
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| Veröffentlicht in: | Journal of pharmaceutical sciences 2001-01, Vol.90 (1), p.70-78 |
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| creator | Hoizey, Guillaume Kaltenbach, Matthieu L. Dukic, Sylvain Lamiable, Denis Lallemand, Aude Millart, Hervé D'Arbigny, Pierre Vistelle, Richard |
| description | The pharmacokinetics of gacyclidine enantiomers, a noncompetitive N‐methyl‐d‐aspartate (NMDA) antagonist, were studied in plasma and spinal cord extracellular fluid (ECF) after experimental spinal cord injury in rats. Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal subdural space. Upon implantation of microdialysis probes in spinal cord (T9) and intravenous (iv) bolus administration of (±)‐gacyclidine (2.5 mg/kg), concentrations in plasma and ECF were monitored over 5 h and analyzed by a stereospecific gas chromatography–mass spectrometry (GC–MS) assay. In plasma, concentrations of (+)‐gacyclidine were ∼25% higher than those of (−)‐gacyclidine over the duration of the experiment and decayed in parallel (t1/2α ∼ 7 min; t1/2β ∼ 90 min) with no significant difference between the two enantiomers. Clearance (CL) and volume of distribution (Vd) of (−)‐gacyclidine were ∼20% higher than those of its optical antipode (CL: 285 versus 236 mL · kg−1 · min−1; Vdβ: 39.3 versus 31.2 l/kg). Protein binding (∼91%) was not stereoselective. In spinal cord ECF, both enantiomers were quantifiable within 10 min after drug administration, and their concentration remained stable over the duration of the experiment in spite of changing blood concentrations. Repeated iv bolus injections of gacyclidine did not modify these profiles. Areas under the curves (AUCs) of concentration in ECF versus time were similar for both enantiomers and not correlated with AUCs in plasma. Penetration of (−)‐gacyclidine was, however, significantly higher (∼30%) than that of (+)‐gacyclidine. In summary, the disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue, and the drug exchange between plasma and spinal cord ECF involves an active transport system. These findings contribute to the explanation of the discrepancy between drug concentrations in plasma and spinal cord ECF. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90: 70–78, 2001 |
| doi_str_mv | 10.1002/1520-6017(200101)90:1<70::AID-JPS8>3.0.CO;2-E |
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Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal subdural space. Upon implantation of microdialysis probes in spinal cord (T9) and intravenous (iv) bolus administration of (±)‐gacyclidine (2.5 mg/kg), concentrations in plasma and ECF were monitored over 5 h and analyzed by a stereospecific gas chromatography–mass spectrometry (GC–MS) assay. In plasma, concentrations of (+)‐gacyclidine were ∼25% higher than those of (−)‐gacyclidine over the duration of the experiment and decayed in parallel (t1/2α ∼ 7 min; t1/2β ∼ 90 min) with no significant difference between the two enantiomers. Clearance (CL) and volume of distribution (Vd) of (−)‐gacyclidine were ∼20% higher than those of its optical antipode (CL: 285 versus 236 mL · kg−1 · min−1; Vdβ: 39.3 versus 31.2 l/kg). Protein binding (∼91%) was not stereoselective. In spinal cord ECF, both enantiomers were quantifiable within 10 min after drug administration, and their concentration remained stable over the duration of the experiment in spite of changing blood concentrations. Repeated iv bolus injections of gacyclidine did not modify these profiles. Areas under the curves (AUCs) of concentration in ECF versus time were similar for both enantiomers and not correlated with AUCs in plasma. Penetration of (−)‐gacyclidine was, however, significantly higher (∼30%) than that of (+)‐gacyclidine. In summary, the disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue, and the drug exchange between plasma and spinal cord ECF involves an active transport system. These findings contribute to the explanation of the discrepancy between drug concentrations in plasma and spinal cord ECF. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90: 70–78, 2001</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1002/1520-6017(200101)90:1<70::AID-JPS8>3.0.CO;2-E</identifier><identifier>PMID: 11064380</identifier><identifier>CODEN: JPMSAE</identifier><language>eng</language><publisher>New York: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Biological Transport, Active ; Calibration ; Cyclohexanes - pharmacokinetics ; Cyclohexenes ; Disease Models, Animal ; Dose-Response Relationship, Drug ; enantiomers ; extracellular fluid ; gacyclidine ; Glutamatergic system (aspartate and other excitatory aminoacids) ; Male ; Medical sciences ; microdialysis ; Neuropharmacology ; Neuroprotective Agents - pharmacokinetics ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Piperidines - pharmacokinetics ; Protein Binding - drug effects ; Rats ; Rats, Wistar ; Spinal Cord Injuries - metabolism ; spinal cord injury ; Stereoisomerism ; Tissue Distribution</subject><ispartof>Journal of pharmaceutical sciences, 2001-01, Vol.90 (1), p.70-78</ispartof><rights>2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association</rights><rights>Copyright © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association</rights><rights>2001 INIST-CNRS</rights><rights>Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90: 70-78, 2001</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c4938-19bc8ae65298f66813efb951d51c4453cd30c879cfcda46596bbcb10f6f54b553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2F1520-6017%28200101%2990%3A1%3C70%3A%3AAID-JPS8%3E3.0.CO%3B2-E$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2F1520-6017%28200101%2990%3A1%3C70%3A%3AAID-JPS8%3E3.0.CO%3B2-E$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,4010,27900,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=939194$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11064380$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hoizey, Guillaume</creatorcontrib><creatorcontrib>Kaltenbach, Matthieu L.</creatorcontrib><creatorcontrib>Dukic, Sylvain</creatorcontrib><creatorcontrib>Lamiable, Denis</creatorcontrib><creatorcontrib>Lallemand, Aude</creatorcontrib><creatorcontrib>Millart, Hervé</creatorcontrib><creatorcontrib>D'Arbigny, Pierre</creatorcontrib><creatorcontrib>Vistelle, Richard</creatorcontrib><title>Distribution of Gacyclidine Enantiomers after Experimental Spinal Cord Injury in Rats: Possible Involvement of an Active Transport System</title><title>Journal of pharmaceutical sciences</title><addtitle>J. Pharm. Sci</addtitle><description>The pharmacokinetics of gacyclidine enantiomers, a noncompetitive N‐methyl‐d‐aspartate (NMDA) antagonist, were studied in plasma and spinal cord extracellular fluid (ECF) after experimental spinal cord injury in rats. Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal subdural space. Upon implantation of microdialysis probes in spinal cord (T9) and intravenous (iv) bolus administration of (±)‐gacyclidine (2.5 mg/kg), concentrations in plasma and ECF were monitored over 5 h and analyzed by a stereospecific gas chromatography–mass spectrometry (GC–MS) assay. In plasma, concentrations of (+)‐gacyclidine were ∼25% higher than those of (−)‐gacyclidine over the duration of the experiment and decayed in parallel (t1/2α ∼ 7 min; t1/2β ∼ 90 min) with no significant difference between the two enantiomers. Clearance (CL) and volume of distribution (Vd) of (−)‐gacyclidine were ∼20% higher than those of its optical antipode (CL: 285 versus 236 mL · kg−1 · min−1; Vdβ: 39.3 versus 31.2 l/kg). Protein binding (∼91%) was not stereoselective. In spinal cord ECF, both enantiomers were quantifiable within 10 min after drug administration, and their concentration remained stable over the duration of the experiment in spite of changing blood concentrations. Repeated iv bolus injections of gacyclidine did not modify these profiles. Areas under the curves (AUCs) of concentration in ECF versus time were similar for both enantiomers and not correlated with AUCs in plasma. Penetration of (−)‐gacyclidine was, however, significantly higher (∼30%) than that of (+)‐gacyclidine. In summary, the disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue, and the drug exchange between plasma and spinal cord ECF involves an active transport system. These findings contribute to the explanation of the discrepancy between drug concentrations in plasma and spinal cord ECF. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90: 70–78, 2001</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Transport, Active</subject><subject>Calibration</subject><subject>Cyclohexanes - pharmacokinetics</subject><subject>Cyclohexenes</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>enantiomers</subject><subject>extracellular fluid</subject><subject>gacyclidine</subject><subject>Glutamatergic system (aspartate and other excitatory aminoacids)</subject><subject>Male</subject><subject>Medical sciences</subject><subject>microdialysis</subject><subject>Neuropharmacology</subject><subject>Neuroprotective Agents - pharmacokinetics</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperidines - pharmacokinetics</subject><subject>Protein Binding - drug effects</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Spinal Cord Injuries - metabolism</subject><subject>spinal cord injury</subject><subject>Stereoisomerism</subject><subject>Tissue Distribution</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqdksGO0zAQhiMEYsvCKyBLSAgOKeM4TuKCkEq3lEJpV7TA0XKcieQlTYqdlu0j8NY4pCoXDojTyJ5vfs_M7yDgFIYUIHpBeQRhAjR9FgFQoM8FjOirFEaj8fwqfH-9zl6zIQwnq5dROL0TDM783WDg66OQ8VhcBA-cuwGABDi_H1xQCknMMhgEP6-Ma63J961patKUZKb0UVemMDWSaa1qf79F64gqW7RkertDa7ZYt6oi652pfZg0tiDz-mZvj8TU5JNq3YhcN86ZvEKfODTVAbuSTl7VZKxbc0Cysap2u8a2ZH10LW4fBvdKVTl8dIqXwee3083kXbhYzeaT8SLUsWBZSEWuM4UJj0RWJklGGZa54LTgVMcxZ7pgoLNU6FIXKk64SPJc5xTKpORxzjm7DJ72ujvbfN-ja-XWOI1VpWps9k6mwLM45cyDH3tQWz-MxVLu_OjKHiUF2Xkju13Lbtey90YKn_ACUnpvZOeNZBLkZCUjOfV6j08P7_MtFn_UTmZ44MkJUE6rqvQL0sadOcEEFbGnlj31w1R4_Pee_tLS77MXDHtB_xPw9iyo7DeZpCzl8utyJtki-7B5E4Ncev5Lz6N36WDQSqcN1hoLY1G3smjMf3XDfgEpvt4B</recordid><startdate>200101</startdate><enddate>200101</enddate><creator>Hoizey, Guillaume</creator><creator>Kaltenbach, Matthieu L.</creator><creator>Dukic, Sylvain</creator><creator>Lamiable, Denis</creator><creator>Lallemand, Aude</creator><creator>Millart, Hervé</creator><creator>D'Arbigny, Pierre</creator><creator>Vistelle, Richard</creator><general>Elsevier Inc</general><general>John Wiley & Sons, Inc</general><general>Wiley</general><general>American Pharmaceutical Association</general><scope>BSCLL</scope><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>7X8</scope></search><sort><creationdate>200101</creationdate><title>Distribution of Gacyclidine Enantiomers after Experimental Spinal Cord Injury in Rats: Possible Involvement of an Active Transport System</title><author>Hoizey, Guillaume ; Kaltenbach, Matthieu L. ; Dukic, Sylvain ; Lamiable, Denis ; Lallemand, Aude ; Millart, Hervé ; D'Arbigny, Pierre ; Vistelle, Richard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4938-19bc8ae65298f66813efb951d51c4453cd30c879cfcda46596bbcb10f6f54b553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Transport, Active</topic><topic>Calibration</topic><topic>Cyclohexanes - pharmacokinetics</topic><topic>Cyclohexenes</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>enantiomers</topic><topic>extracellular fluid</topic><topic>gacyclidine</topic><topic>Glutamatergic system (aspartate and other excitatory aminoacids)</topic><topic>Male</topic><topic>Medical sciences</topic><topic>microdialysis</topic><topic>Neuropharmacology</topic><topic>Neuroprotective Agents - pharmacokinetics</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidines - pharmacokinetics</topic><topic>Protein Binding - drug effects</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Spinal Cord Injuries - metabolism</topic><topic>spinal cord injury</topic><topic>Stereoisomerism</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hoizey, Guillaume</creatorcontrib><creatorcontrib>Kaltenbach, Matthieu L.</creatorcontrib><creatorcontrib>Dukic, Sylvain</creatorcontrib><creatorcontrib>Lamiable, Denis</creatorcontrib><creatorcontrib>Lallemand, Aude</creatorcontrib><creatorcontrib>Millart, Hervé</creatorcontrib><creatorcontrib>D'Arbigny, Pierre</creatorcontrib><creatorcontrib>Vistelle, Richard</creatorcontrib><collection>Istex</collection><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>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hoizey, Guillaume</au><au>Kaltenbach, Matthieu L.</au><au>Dukic, Sylvain</au><au>Lamiable, Denis</au><au>Lallemand, Aude</au><au>Millart, Hervé</au><au>D'Arbigny, Pierre</au><au>Vistelle, Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distribution of Gacyclidine Enantiomers after Experimental Spinal Cord Injury in Rats: Possible Involvement of an Active Transport System</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J. Pharm. Sci</addtitle><date>2001-01</date><risdate>2001</risdate><volume>90</volume><issue>1</issue><spage>70</spage><epage>78</epage><pages>70-78</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><coden>JPMSAE</coden><abstract>The pharmacokinetics of gacyclidine enantiomers, a noncompetitive N‐methyl‐d‐aspartate (NMDA) antagonist, were studied in plasma and spinal cord extracellular fluid (ECF) after experimental spinal cord injury in rats. Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal subdural space. Upon implantation of microdialysis probes in spinal cord (T9) and intravenous (iv) bolus administration of (±)‐gacyclidine (2.5 mg/kg), concentrations in plasma and ECF were monitored over 5 h and analyzed by a stereospecific gas chromatography–mass spectrometry (GC–MS) assay. In plasma, concentrations of (+)‐gacyclidine were ∼25% higher than those of (−)‐gacyclidine over the duration of the experiment and decayed in parallel (t1/2α ∼ 7 min; t1/2β ∼ 90 min) with no significant difference between the two enantiomers. Clearance (CL) and volume of distribution (Vd) of (−)‐gacyclidine were ∼20% higher than those of its optical antipode (CL: 285 versus 236 mL · kg−1 · min−1; Vdβ: 39.3 versus 31.2 l/kg). Protein binding (∼91%) was not stereoselective. In spinal cord ECF, both enantiomers were quantifiable within 10 min after drug administration, and their concentration remained stable over the duration of the experiment in spite of changing blood concentrations. Repeated iv bolus injections of gacyclidine did not modify these profiles. Areas under the curves (AUCs) of concentration in ECF versus time were similar for both enantiomers and not correlated with AUCs in plasma. Penetration of (−)‐gacyclidine was, however, significantly higher (∼30%) than that of (+)‐gacyclidine. In summary, the disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue, and the drug exchange between plasma and spinal cord ECF involves an active transport system. These findings contribute to the explanation of the discrepancy between drug concentrations in plasma and spinal cord ECF. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90: 70–78, 2001</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>11064380</pmid><doi>10.1002/1520-6017(200101)90:1<70::AID-JPS8>3.0.CO;2-E</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Biological Transport, Active Calibration Cyclohexanes - pharmacokinetics Cyclohexenes Disease Models, Animal Dose-Response Relationship, Drug enantiomers extracellular fluid gacyclidine Glutamatergic system (aspartate and other excitatory aminoacids) Male Medical sciences microdialysis Neuropharmacology Neuroprotective Agents - pharmacokinetics Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Piperidines - pharmacokinetics Protein Binding - drug effects Rats Rats, Wistar Spinal Cord Injuries - metabolism spinal cord injury Stereoisomerism Tissue Distribution |
| title | Distribution of Gacyclidine Enantiomers after Experimental Spinal Cord Injury in Rats: Possible Involvement of an Active Transport System |
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