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
Hauptverfasser: Thakur, Ashish, Kadam, Rajendra S, Kompella, Uday B
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Kompella, Uday B
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 &gt; retina &gt; 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). 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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. 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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 &gt; retina &gt; 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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ispartof Drug metabolism and disposition, 2011-05, Vol.39 (5), p.771-781
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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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