Potential pharmacokinetic role of organic cation transporters in modulating the transcorneal penetration of its substrates administered topically

Nirmal, Jayabalan; Singh, Sundararajan Baskar; Biswas, Nihar Ranjan; Thavaraj, Vasantha; Azad, Rajvardhan; Velpandian, Thirumurthy

doi:10.1038/eye.2013.146

Cited by 18 publications

(8 citation statements)

References 39 publications

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“…Furthermore, considering that zebrafish do not have an OCT3 ortholog, it is possible that Oct1 and 2 transporters in zebrafish compensate for the function of Oct3, especially considering extensive substrate overlap among mammalian OCT1, 2 and 3 [ 4 , 51 , 53 ]. This assumption is additionally supported by the highest expression of oct2 in comparison to other examined slc22 transcripts in zebrafish eye, which is similar to expression of human and murine OCT3/Oct3 in the eye, where it plays an important role in absorption, distribution and clearance of various xenobiotic substrates [ 54 , 55 ]. Organic cation transporters also showed gender dependent differences in tissue expression.…”

Section: Discussionmentioning

confidence: 83%

Phylogenetic, syntenic, and tissue expression analysis of slc22 genes in zebrafish (Danio rerio)

et al. 2016

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BackgroundSLC22 protein family is a member of the SLC (Solute carriers) superfamily of polyspecific membrane transporters responsible for uptake of a wide range of organic anions and cations, including numerous endo- and xenobiotics. Due to the lack of knowledge on zebrafish Slc22 family, we performed initial characterization of these transporters using a detailed phylogenetic and conserved synteny analysis followed by the tissue specific expression profiling of slc22 transcripts.ResultsWe identified 20 zebrafish slc22 genes which are organized in the same functional subgroups as human SLC22 members. Orthologies and syntenic relations between zebrafish and other vertebrates revealed consequences of the teleost-specific whole genome duplication as shown through one-to-many orthologies for certain zebrafish slc22 genes. Tissue expression profiles of slc22 transcripts were analyzed using qRT-PCR determinations in nine zebrafish tissues: liver, kidney, intestine, gills, brain, skeletal muscle, eye, heart, and gonads. Our analysis revealed high expression of oct1 in kidney, especially in females, followed by oat3 and oat2c in females, oat2e in males and orctl4 in females. oct1 was also dominant in male liver. oat2d showed the highest expression in intestine with less noticeable gender differences. All slc22 genes showed low expression in gills, and moderate expression in heart and skeletal muscle. Dominant genes in brain were oat1 in females and oct1 in males, while the highest gender differences were determined in gonads, with dominant expression of almost all slc22 genes in testes and the highest expression of oat2a.ConclusionsOur study offers the first insight into the orthology relationships, gene expression and potential role of Slc22 membrane transporters in zebrafish. Clear orthological relationships of zebrafish slc22 and other vertebrate slc22 genes were established. slc22 members are mostly highly conserved, suggesting their physiological and toxicological importance. One-to-many orthologies and differences in tissue expression patterns of zebrafish slc22 genes in comparison to human orthologs were observed. Our expression data point to partial similarity of zebrafish versus human Slc22 members, with possible compensatory roles of certain zebrafish transporters, whereas higher number of some orthologs implies potentially more diverse and specific roles of these proteins in zebrafish.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2981-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 83%

Phylogenetic, syntenic, and tissue expression analysis of slc22 genes in zebrafish (Danio rerio)

et al. 2016

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“…These findings indicate that the ocular absorption of timolol might be affected by brimonidine, but not by differences in formulation compositions, such as preservatives, for the above-described reason. Transporters in the corneal epithelium have been reported to module the ocular bioavailability of their substrates administered topically [29]. However, enhanced timolol concentration in the aqueous humor may not be caused by the transporter effect because Sakanaka et al [30] reported that timolol permeation through the corneal epithelium was predominantly contributed by passive diffusion.…”

Section: Discussionmentioning

confidence: 99%

Ocular and Systemic Pharmacokinetics of Brimonidine and Timolol After Topical Administration in Rabbits: Comparison Between Fixed-Combination and Single Drugs

et al. 2020

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Introduction: This study was aimed to compare ocular tissue distribution and systemic exposure of brimonidine and timolol after single topical administration to rabbits of fixed-combination ophthalmic solution of 0.1% brimonidine tartrate and 0.5% timolol and single drugs (0.1% brimonidine tartrate ophthalmic solution or 0.5% timolol ophthalmic solution) or concomitant administration of single drugs. Methods: Rabbits were treated with a single topical administration of each ophthalmic solution or concomitant administration of single drugs. For concomitant administration, 0.1% brimonidine tartrate was administered after 0.5% timolol instillation successively within 10 s (without interval) or with 5-min intervals. Brimonidine and timolol concentrations in the aqueous humor, retina/choroid, vitreous body, and plasma were determined with liquid chromatography-tandem mass spectrometry.

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“…Only a few influx transporters have been subjected to functional studies in the cornea, even though expression of several transporters has been reported ( Table 1). The organic cation transporters (Octs) were studied in rabbits in vivo [32]. Oct substrates, tetraethylammonium (TEA) or metformin were administered topically followed by closing of the eyelids after dosing.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Expression, activity and pharmacokinetic impact of ocular transporters

Vellonen

Hellinen

Mannermaa

et al. 2018

Advanced Drug Delivery Reviews

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The eye is protected by several tissues that limit the permeability and entry of potentially harmful substances, but also hamper the delivery of drugs in the treatment of ocular diseases. Active transport across the ocular barriers may affect drug distribution, but the impact of drug transporters on ocular drug delivery is not well known. We have collected and critically reviewed the literature for ocular expression and activity of known drug transporters. The review concentrates on drug transporters that have been functionally characterized in ocular tissues or primary cells and on transporters for which there is available expression data at the protein level. Species differences are highlighted, since these may explain observed inconsistencies in the influence of specific transporters on drug disposition. There is variable evidence about the pharmacokinetic role of transporters in ocular tissues. The strongest evidence for the role of active transport is available for the blood-retinal barrier. We explored the role of active transport in the cornea and blood retinal barrier with pharmacokinetic simulations. The simulations show that the active transport is important only in the case of specific parameter combinations.

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Potential pharmacokinetic role of organic cation transporters in modulating the transcorneal penetration of its substrates administered topically

Cited by 18 publications

References 39 publications

Phylogenetic, syntenic, and tissue expression analysis of slc22 genes in zebrafish (Danio rerio)

Phylogenetic, syntenic, and tissue expression analysis of slc22 genes in zebrafish (Danio rerio)

Ocular and Systemic Pharmacokinetics of Brimonidine and Timolol After Topical Administration in Rabbits: Comparison Between Fixed-Combination and Single Drugs

Expression, activity and pharmacokinetic impact of ocular transporters

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