Cassette analysis of eight beta-blockers in bovine eye sclera, choroid–RPE, retina, and vitreous by liquid chromatography–tandem mass spectrometry

Kadam, Rajendra S.; Kompella, Uday B.

doi:10.1016/j.jchromb.2008.12.027

Cited by 30 publications

(8 citation statements)

References 24 publications

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“…The ␤-blocker concentrations in bovine and rat ocular tissues were estimated after liquid-liquid extraction of drug from tissues as described previously (Kadam and Kompella, 2009). In brief, the ocular tissue samples were homogenized with 500 l of 2% (wt/v) solution of NaOH in water and Tissue Tearor (Biospec Products).…”

Section: Methodsmentioning

confidence: 99%

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Kadam

Kompella

2009

J Pharmacol Exp Ther

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In vitro bovine eye tissue/phosphate-buffered saline, pH 7.4, partition coefficients (Kt:b), in vitro binding to natural melanin, and in vivo delivery at 1 h after posterior subconjunctival injection in Brown Norway rats were determined for eight ␤-blockers. The Kt:b was in the order intact tissue, dry weight method Ն intact tissue, wet weight method corrected for tissue water and drug in tissue water Ͼ Ͼ intact tissue, wet weight method Ͼ homogenized tissue. In intact tissue methods, Kt:b followed the order choroid-retinal pigment epithelium (RPE) Ͼ trabecular meshwork Ͼ retina Ͼ sclera ϳ optic nerve; propranolol Ͼ betaxolol Ͼ pindolol ϳ timolol ϳ metoprolol Ͼ sotalol ϳ atenolol ϳ nadolol. Intact tissue, wet weight log (Kt:b) correlated positively with log D for all tissues (R 2 of 0.7-0.9). Log (melanin binding capacity) correlated positively with choroid-RPE log (Kt:b) (R 2 of 0.5). With an increase in concentration, Kt:b decreased in trabecular meshwork for all ␤-blockers and for some lipophilic ␤-blockers in choroid-RPE and sclera. With an increase in drug lipophilicity, in vivo tissue distribution increased in choroid-RPE, iris-ciliary body, sclera, and cornea but exhibited a declining trend in retina, vitreous, and lens. In vitro bovine intact tissue, wet weight Kt:b correlated positively with rat in vivo tissue/vitreous humor distribution for sclera, choroid-RPE, and retina (R 2 of 0.985-0.993). In vitro tissue partition coefficients might be useful in predicting in vivo drug distribution after trans-scleral delivery. Less lipophilic solutes exhibiting limited nonproductive binding in choroid-RPE might exhibit greater transscleral delivery to the retina and vitreous.

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Section: Methodsmentioning

confidence: 99%

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Kadam

Kompella

2009

J Pharmacol Exp Ther

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“…Transport of transporter-specific substrates was carried out across human SCRPE for evaluation of functional activity of transporters in SCRPE barriers. Because of the limited availability of human eyes, a cassette dosing approach was used to reduce the tissue use and increase the throughput (Kadam and Kompella, 2009). The effect of directionality was evaluated to determine whether a particular transporter contributes to the influx of drug into the retina or efflux from the retina.…”

Section: Patient Demographics and Hande Staining Of Human Eyesmentioning

confidence: 99%

RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

2012

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Since there is paucity of information on solute transporters in human ocular tissues, the aim of this study was immunohistochemical and functional characterization of peptide transporters (PEPT), organic cation transporters (OCTs), neutral and basic amino acid transporters (ATB 0,+ ), and monocarboxylate transporters (MCTs) in human ocular barriers. Immunohistochemical localization of transporters was achieved using 5-mm-thick paraffin-embedded sections of whole human eyes. In vitro transport studies were carried out across human cornea and sclera-choroid-retinal pigment epithelium (SCRPE) using a cassette of specific substrates in the presence and absence of inhibitors to determine the role of transporters in transtissue solute delivery. Immunohistochemistry showed the expression of PEPT-1, PEPT-2, ATB 0,+

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“…Beta-blocker quantification in both mitochondrial tissue and buffer samples were analyzed using a previously published method (17). Analyte separation was accomplished using Hypersil-ODS C18 column (100×2.1 mm, 3.5 µm) with gradient elution at a flow rate of 0.4 ml/min with a mobile phase containing 5 mM ammonium formate, pH 3.5 (A) and acetonitrile methanol (75:25 v/v) containing 0.02% triethyl amine, pH 3.5 (B).…”

Section: Methodsmentioning

confidence: 99%

Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties

et al. 2011

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Purpose To determine the influence of drug physicochemical properties on brain mitochondrial delivery of 20 drugs at physiological pH. Methods The delivery of 8 cationic drugs (beta-blockers), 6 neutral drugs (corticosteroids), and 6 anionic drugs (non-steroidal anti-inflammatory drugs, NSAIDs) to isolated rat brain mitochondria was determined with and without membrane depolarization. Multiple linear regression was used to determine whether lipophilicity (Log D), charge, polarizability, polar surface area (PSA), and molecular weight influence mitochondrial delivery. Results The Log D for beta-blockers, corticosteroids, and NSAIDs was in the range of −1.41 to 1.37, 0.72 to 2.97, and −0.98 to 2, respectively. The % mitochondrial uptake increased exponentially with an increase in Log D for each class of drugs, with the uptake at a given lipophilicity obeying the rank order cationic>anionic>neutral. Valinomycin reduced membrane potential and the delivery of positively charged propranolol and betaxolol. The best equation for the combined data set was Log % Uptake=0.333 Log D+ 0.157 Charge – 0.887 Log PSA+2.032 (R2=0.738). Conclusions Drug lipopohilicity, charge, and polar surface area and membrane potential influence mitochondrial drug delivery, with the uptake of positively charged, lipophilic molecules being the most efficient.

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Cassette analysis of eight beta-blockers in bovine eye sclera, choroid–RPE, retina, and vitreous by liquid chromatography–tandem mass spectrometry

Cited by 30 publications

References 24 publications

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties

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