Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids
The influence of drug properties including solubility, lipophilicity, tissue partition coefficients, and in vitro transscleral permeability on ex vivo and in vivo transscleral delivery from corticosteroid suspensions was determined. Solubility, tissue/buffer partition coefficients for bovine sclera...
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Veröffentlicht in: | Drug metabolism and disposition 2011-05, Vol.39 (5), p.771-781 |
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description | The influence of drug properties including solubility, lipophilicity, tissue partition coefficients, and in vitro transscleral permeability on ex vivo and in vivo transscleral delivery from corticosteroid suspensions was determined. Solubility, tissue/buffer partition coefficients for bovine sclera and choroid-retinal pigment epithelium (CRPE), and in vitro bovine sclera and sclera-choroid-retinal pigment epithelium (SCRPE) transscleral transport were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide in solution. Ex vivo and in vivo transscleral delivery was assessed in Brown Norway rats after posterior subconjunctival injection of a 1 mg/ml suspension of each corticosteroid. Corticosteroid solubility and partition coefficients ranged from ∼ 17 to 300 μg/ml and 3.0 to 11.4 for sclera and from 7.1 to 35.8 for CRPE, respectively, with the more lipophilic molecules partitioning more into both tissues. Transport across sclera and SCRPE was in the range of 3.9 to 10.7% and 0.3 to 1.8%, respectively, with the transport declining with an increase in lipophilicity. Ex vivo and in vivo transscleral delivery indicated tissue distribution in the order CRPE ≥ sclera > retina > vitreous. Tissue partitioning showed a positive correlation with drug lipophilicity (R(2) = 0.66-0.96). Ex vivo and in vivo sclera, CRPE, retina, and vitreous tissue levels of all corticosteroids showed strong positive correlation with drug solubility (R(2) = 0.91-1.0) but not lipophilicity (R(2) = 0.24-0.41) or tissue partitioning (R(2) = 0.24-0.46) when delivered as suspensions. In vivo delivery was lower in all eye tissues assessed than ex vivo delivery, with the in vivo/ex vivo ratios being the lowest in the vitreous (0.085-0.212). Upon exposure to corticosteroid suspensions ex vivo or in vivo, transscleral intraocular tissue distribution was primarily driven by the drug solubility. |
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Solubility, tissue/buffer partition coefficients for bovine sclera and choroid-retinal pigment epithelium (CRPE), and in vitro bovine sclera and sclera-choroid-retinal pigment epithelium (SCRPE) transscleral transport were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide in solution. Ex vivo and in vivo transscleral delivery was assessed in Brown Norway rats after posterior subconjunctival injection of a 1 mg/ml suspension of each corticosteroid. Corticosteroid solubility and partition coefficients ranged from ∼ 17 to 300 μg/ml and 3.0 to 11.4 for sclera and from 7.1 to 35.8 for CRPE, respectively, with the more lipophilic molecules partitioning more into both tissues. Transport across sclera and SCRPE was in the range of 3.9 to 10.7% and 0.3 to 1.8%, respectively, with the transport declining with an increase in lipophilicity. Ex vivo and in vivo transscleral delivery indicated tissue distribution in the order CRPE ≥ sclera > retina > vitreous. Tissue partitioning showed a positive correlation with drug lipophilicity (R(2) = 0.66-0.96). Ex vivo and in vivo sclera, CRPE, retina, and vitreous tissue levels of all corticosteroids showed strong positive correlation with drug solubility (R(2) = 0.91-1.0) but not lipophilicity (R(2) = 0.24-0.41) or tissue partitioning (R(2) = 0.24-0.46) when delivered as suspensions. In vivo delivery was lower in all eye tissues assessed than ex vivo delivery, with the in vivo/ex vivo ratios being the lowest in the vitreous (0.085-0.212). Upon exposure to corticosteroid suspensions ex vivo or in vivo, transscleral intraocular tissue distribution was primarily driven by the drug solubility.</description><identifier>ISSN: 0090-9556</identifier><identifier>EISSN: 1521-009X</identifier><identifier>DOI: 10.1124/dmd.110.037408</identifier><identifier>PMID: 21346004</identifier><language>eng</language><publisher>United States: The American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Adrenal Cortex Hormones - administration & dosage ; Adrenal Cortex Hormones - chemistry ; Adrenal Cortex Hormones - pharmacokinetics ; Animals ; Biological Transport ; Cattle ; Choroid - drug effects ; Choroid - metabolism ; Eye - drug effects ; Eye - metabolism ; Injections ; Male ; Permeability ; Pigment Epithelium of Eye - drug effects ; Pigment Epithelium of Eye - metabolism ; Rats ; Retina - drug effects ; Retina - metabolism ; Sclera - drug effects ; Sclera - metabolism ; Solubility ; Suspensions ; Tissue Distribution</subject><ispartof>Drug metabolism and disposition, 2011-05, Vol.39 (5), p.771-781</ispartof><rights>Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-ae5553fc8094098e44506597b7f5b6fbd9b599c923a1259a4a0e0e1b9d570b583</citedby><cites>FETCH-LOGICAL-c389t-ae5553fc8094098e44506597b7f5b6fbd9b599c923a1259a4a0e0e1b9d570b583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21346004$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thakur, Ashish</creatorcontrib><creatorcontrib>Kadam, Rajendra S</creatorcontrib><creatorcontrib>Kompella, Uday B</creatorcontrib><title>Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids</title><title>Drug metabolism and disposition</title><addtitle>Drug Metab Dispos</addtitle><description>The influence of drug properties including solubility, lipophilicity, tissue partition coefficients, and in vitro transscleral permeability on ex vivo and in vivo transscleral delivery from corticosteroid suspensions was determined. Solubility, tissue/buffer partition coefficients for bovine sclera and choroid-retinal pigment epithelium (CRPE), and in vitro bovine sclera and sclera-choroid-retinal pigment epithelium (SCRPE) transscleral transport were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide in solution. Ex vivo and in vivo transscleral delivery was assessed in Brown Norway rats after posterior subconjunctival injection of a 1 mg/ml suspension of each corticosteroid. Corticosteroid solubility and partition coefficients ranged from ∼ 17 to 300 μg/ml and 3.0 to 11.4 for sclera and from 7.1 to 35.8 for CRPE, respectively, with the more lipophilic molecules partitioning more into both tissues. Transport across sclera and SCRPE was in the range of 3.9 to 10.7% and 0.3 to 1.8%, respectively, with the transport declining with an increase in lipophilicity. Ex vivo and in vivo transscleral delivery indicated tissue distribution in the order CRPE ≥ sclera > retina > vitreous. Tissue partitioning showed a positive correlation with drug lipophilicity (R(2) = 0.66-0.96). Ex vivo and in vivo sclera, CRPE, retina, and vitreous tissue levels of all corticosteroids showed strong positive correlation with drug solubility (R(2) = 0.91-1.0) but not lipophilicity (R(2) = 0.24-0.41) or tissue partitioning (R(2) = 0.24-0.46) when delivered as suspensions. In vivo delivery was lower in all eye tissues assessed than ex vivo delivery, with the in vivo/ex vivo ratios being the lowest in the vitreous (0.085-0.212). Upon exposure to corticosteroid suspensions ex vivo or in vivo, transscleral intraocular tissue distribution was primarily driven by the drug solubility.</description><subject>Adrenal Cortex Hormones - administration & dosage</subject><subject>Adrenal Cortex Hormones - chemistry</subject><subject>Adrenal Cortex Hormones - pharmacokinetics</subject><subject>Animals</subject><subject>Biological Transport</subject><subject>Cattle</subject><subject>Choroid - drug effects</subject><subject>Choroid - metabolism</subject><subject>Eye - drug effects</subject><subject>Eye - metabolism</subject><subject>Injections</subject><subject>Male</subject><subject>Permeability</subject><subject>Pigment Epithelium of Eye - drug effects</subject><subject>Pigment Epithelium of Eye - metabolism</subject><subject>Rats</subject><subject>Retina - drug effects</subject><subject>Retina - metabolism</subject><subject>Sclera - drug effects</subject><subject>Sclera - metabolism</subject><subject>Solubility</subject><subject>Suspensions</subject><subject>Tissue Distribution</subject><issn>0090-9556</issn><issn>1521-009X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkF1LwzAUhoMobk5vvZT-gc6TJmmbG0GGXzDwRsG7kCbpFsmakrTD_XszpkOv3vP5nsOD0DWGOcYFvdUbnQKYA6ko1CdoilmBcwD-cYqmSSDnjJUTdBHjJwCmlPBzNCkwoSUAnaL2pWvdaDplMt9mOoyrLHo3NtbZYZfJTmfO9r5fp1ztK77LhiC7GJUzQbosmMF2SbVxdmvCbu8S7VemfBis8nEwwVsdL9FZK100Vz86Q--PD2-L53z5-vSyuF_mitR8yKVhjJFW1cAp8NpQyqBkvGqqljVl22jeMM4VL4jEBeOSSjBgcMM1q6BhNZmhu4NvPzYbo5Xp0rdO9MFuZNgJL6343-nsWqz8VhCoi4QwGcwPBir4GINpj7sYxJ64SMRTAOJAPC3c_L14HP9FTL4B_3eAKQ</recordid><startdate>20110501</startdate><enddate>20110501</enddate><creator>Thakur, Ashish</creator><creator>Kadam, Rajendra S</creator><creator>Kompella, Uday B</creator><general>The American Society for Pharmacology and Experimental Therapeutics</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>5PM</scope></search><sort><creationdate>20110501</creationdate><title>Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids</title><author>Thakur, Ashish ; Kadam, Rajendra S ; Kompella, Uday B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-ae5553fc8094098e44506597b7f5b6fbd9b599c923a1259a4a0e0e1b9d570b583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adrenal Cortex Hormones - administration & dosage</topic><topic>Adrenal Cortex Hormones - chemistry</topic><topic>Adrenal Cortex Hormones - pharmacokinetics</topic><topic>Animals</topic><topic>Biological Transport</topic><topic>Cattle</topic><topic>Choroid - drug effects</topic><topic>Choroid - metabolism</topic><topic>Eye - drug effects</topic><topic>Eye - metabolism</topic><topic>Injections</topic><topic>Male</topic><topic>Permeability</topic><topic>Pigment Epithelium of Eye - drug effects</topic><topic>Pigment Epithelium of Eye - metabolism</topic><topic>Rats</topic><topic>Retina - drug effects</topic><topic>Retina - metabolism</topic><topic>Sclera - drug effects</topic><topic>Sclera - metabolism</topic><topic>Solubility</topic><topic>Suspensions</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thakur, Ashish</creatorcontrib><creatorcontrib>Kadam, Rajendra S</creatorcontrib><creatorcontrib>Kompella, Uday B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Drug metabolism and disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thakur, Ashish</au><au>Kadam, Rajendra S</au><au>Kompella, Uday B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids</atitle><jtitle>Drug metabolism and disposition</jtitle><addtitle>Drug Metab Dispos</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>39</volume><issue>5</issue><spage>771</spage><epage>781</epage><pages>771-781</pages><issn>0090-9556</issn><eissn>1521-009X</eissn><abstract>The influence of drug properties including solubility, lipophilicity, tissue partition coefficients, and in vitro transscleral permeability on ex vivo and in vivo transscleral delivery from corticosteroid suspensions was determined. Solubility, tissue/buffer partition coefficients for bovine sclera and choroid-retinal pigment epithelium (CRPE), and in vitro bovine sclera and sclera-choroid-retinal pigment epithelium (SCRPE) transscleral transport were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide in solution. Ex vivo and in vivo transscleral delivery was assessed in Brown Norway rats after posterior subconjunctival injection of a 1 mg/ml suspension of each corticosteroid. Corticosteroid solubility and partition coefficients ranged from ∼ 17 to 300 μg/ml and 3.0 to 11.4 for sclera and from 7.1 to 35.8 for CRPE, respectively, with the more lipophilic molecules partitioning more into both tissues. Transport across sclera and SCRPE was in the range of 3.9 to 10.7% and 0.3 to 1.8%, respectively, with the transport declining with an increase in lipophilicity. Ex vivo and in vivo transscleral delivery indicated tissue distribution in the order CRPE ≥ sclera > retina > vitreous. Tissue partitioning showed a positive correlation with drug lipophilicity (R(2) = 0.66-0.96). Ex vivo and in vivo sclera, CRPE, retina, and vitreous tissue levels of all corticosteroids showed strong positive correlation with drug solubility (R(2) = 0.91-1.0) but not lipophilicity (R(2) = 0.24-0.41) or tissue partitioning (R(2) = 0.24-0.46) when delivered as suspensions. In vivo delivery was lower in all eye tissues assessed than ex vivo delivery, with the in vivo/ex vivo ratios being the lowest in the vitreous (0.085-0.212). Upon exposure to corticosteroid suspensions ex vivo or in vivo, transscleral intraocular tissue distribution was primarily driven by the drug solubility.</abstract><cop>United States</cop><pub>The American Society for Pharmacology and Experimental Therapeutics</pub><pmid>21346004</pmid><doi>10.1124/dmd.110.037408</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adrenal Cortex Hormones - administration & dosage Adrenal Cortex Hormones - chemistry Adrenal Cortex Hormones - pharmacokinetics Animals Biological Transport Cattle Choroid - drug effects Choroid - metabolism Eye - drug effects Eye - metabolism Injections Male Permeability Pigment Epithelium of Eye - drug effects Pigment Epithelium of Eye - metabolism Rats Retina - drug effects Retina - metabolism Sclera - drug effects Sclera - metabolism Solubility Suspensions Tissue Distribution |
title | Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids |
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