Topical ocular pharmacokinetics and bioavailability for a cocktail of atenolol, timolol and betaxolol in rabbits

Fayyaz, Anam; Ranta, Veli‐Pekka; Toropainen, Elisa; Vellonen, Kati‐Sisko; Valtari, Annika; Puranen, Jooseppi; Ruponen, Marika; Gardner, Iain; Urtti, Arto; Jamei, Masoud; Amo, Eva M. del

doi:10.1016/j.ejps.2020.105553

Cited by 29 publications

(13 citation statements)

References 19 publications

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“…25 However, after application in the viscous vehicle, the bioavailability of brinzolamide in the aqueous humor was only 0.10%, which is 15e43 times less than the bioavailability of timolol and betaxolol after instillation in simple non-viscous buffer solutions. 24 Porcine corneal permeability values of atenolol (1.72 ± 0.87 Â 10 À7 cm/s) and brinzolamide (1.36 ± 0.35 Â 10 À7 cm/s) are similar 9,10 and ocular bioavailability of these two drugs were in the same range (0.10% vs. 0.07%). Atenolol formulation is a simple solution, whereas brinzolamide is applied as a viscous suspension.…”

Section: Discussionmentioning

confidence: 87%

“…While there are many reports on the pharmacokinetics of topical eye drops, information on absolute drug bioavailability in the aqueous humor is sparse. Recently the aqueous humor bioavailability of topical ophthalmic solutions of atenolol, timolol and betaxolol has been reported with values from 0.07 to 4.31% 24 representingã 60-fold, range of bioavailability.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive Ocular and Systemic Pharmacokinetics of Brinzolamide in Rabbits After Intracameral, Topical, and Intravenous Administration

Naageshwaran

Ranta

Gum

et al. 2021

Journal of Pharmaceutical Sciences

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Brinzolamide is a topical carbonic anhydrase inhibitor which reduces the production of aqueous humor in the ciliary body, thereby reducing intra-ocular pressure. It is formulated as an ophthalmic suspension. The pharmacokinetics of ocular suspensions is not well understood. The objective of this study was to characterize the pharmacokinetics of brinzolamide in rabbit aqueous humor, iris-ciliary body, plasma, and whole blood. New Zealand White rabbits were dosed via intracameral, topical and intravenous administration. After intracameral administration (4.5 mg) of solubilized brinzolamide, aqueous humor concentrations were described with a two-compartment model, the estimated clearance was 4.12 mL/ min, apparent volume of distribution at steady-state 673 mL, and terminal half-life 3.4 h. After topical administration of 1% brinzolamide suspension (500 mg), absolute bioavailability based on aqueous humor AUC 0-∞ was 0.10%. After intravenous administration of brinzolamide solution (0.75 mg/kg) elimination half-life in plasma and whole blood appeared to be over two weeks. The ratios of the measured concentrations of irisciliary body to whole blood, to plasma, and to aqueous humor concentrations enabled direct comparisons, and helped identify the significant contribution of the conjunctival-scleral pathways of absorption to the ciliary body. This study shows for the first-time the absolute bioavailability in aqueous humor and provides comprehensive pharmacokinetic parameters following administration of a topical suspension.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Comprehensive Ocular and Systemic Pharmacokinetics of Brinzolamide in Rabbits After Intracameral, Topical, and Intravenous Administration

Naageshwaran

Ranta

Gum

et al. 2021

Journal of Pharmaceutical Sciences

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“…The iris-ciliary muscle vessels constitute the outer BAB (excluding the ciliary process vessels). Therefore, the clearance will be faster for lipophilic drugs more able to cross the BAB than hydrophilic drugs (Figure 2) (Fayyaz et al, 2020a;Fayyaz et al, 2020b). Drug diffusion from the irisciliary body back to the aqueous humor is unlikely for lipophilic drugs but may occur for compounds that are hydrophilic or have low permeability properties across biological membranes (e.g., atenolol or brinzolamide) (Fayyaz et al, 2020a;Naageshwaran et al, 2021).…”

Section: Corneal Absorption Routementioning

confidence: 99%

Topical ophthalmic administration: Can a drug instilled onto the ocular surface exert an effect at the back of the eye?

Amo

2022

Front. Drug. Deliv.

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Topical ophthalmic instillation is an appealing strategy to deliver drugs to the back of the eye to treat retinal diseases such as neovascular age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and glaucomatous optic neuropathy. It has several advantages such as being non-invasive and user-friendly, e.g., allowing self-administration. However, the main obstacle has been how to achieve therapeutic drug concentrations in the retina due to the eye’s protective mechanisms, flows, and barriers. Less than 4% of the instilled drug dose enters the anterior chamber, and much less is expected to reach the posterior segment. It is crucial to understand a drug’s topical pharmacokinetics in humans and how one can extrapolate data from rabbits to humans. In this review, the available data on the retina and vitreous drug concentrations from pharmacokinetics studies conducted in human patients and rabbits have been compiled, together with the critical physiological factors to be considered for this route of administration. Improvements in the design of preclinical studies are suggested to increase their translatability to the treatment of human patients. Finally, the current status of clinical trials with topical ophthalmic formulations intended to treat the back of the eye is depicted. At present, no topical ophthalmic formulations to treat neovascular age-related macular degeneration or other retinal neurodegenerative illnesses have reached the market.

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“…Topical eye drops are the most commonly used dosage form in the treatment of anterior segment eye diseases [ 1 , 2 ]. Topical drug administration is, however, limited by the low ocular bioavailability [ 3 , 4 ]. For example, 0.07–4.3% of the topically instilled beta-blocking drugs reached the aqueous humor of the rabbit eye [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Topical drug administration is, however, limited by the low ocular bioavailability [ 3 , 4 ]. For example, 0.07–4.3% of the topically instilled beta-blocking drugs reached the aqueous humor of the rabbit eye [ 3 ]. Low ocular bioavailability is due to the short retention time (a few minutes) [ 5 , 6 , 7 ] and tight permeation barriers of corneal and conjunctival epithelia on the ocular surface [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Partitioning and Spatial Distribution of Drugs in Ocular Surface Tissues

et al. 2021

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Ocular drug absorption after eye drop instillation has been widely studied, but partitioning phenomena and spatial drug distribution are poorly understood. We investigated partitioning of seven beta-blocking drugs in corneal epithelium, corneal stroma, including endothelium and conjunctiva, using isolated porcine tissues and cultured human corneal epithelial cells. The chosen beta-blocking drugs had a wide range (−1.76–0.79) of n-octanol/buffer solution distribution coefficients at pH 7.4 (Log D7.4). In addition, the ocular surface distribution of three beta-blocking drugs was determined by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) after their simultaneous application in an eye drop to the rabbits in vivo. Studies with isolated porcine corneas revealed that the distribution coefficient (Kp) between the corneal epithelium and donor solution showed a positive relationship and good correlation with Log D7.4 and about a 50-fold range of Kp values (0.1–5). On the contrary, Kp between corneal stroma and epithelium showed an inverse (negative) relationship and correlation with Log D7.4 based on a seven-fold range of Kp values. In vitro corneal cell uptake showed a high correlation with the ex vivo corneal epithelium/donor Kp values. Partitioning of the drugs into the porcine conjunctiva also showed a positive relationship with lipophilicity, but the range of Kp values was less than with the corneal epithelium. MALDI-IMS allowed simultaneous detection of three compounds in the cornea, showed data in line with other experiments, and revealed uneven spatial drug distribution in the cornea. Our data indicate the importance of lipophilicity in defining the corneal pharmacokinetics and the Kp values are a useful building block in the kinetic simulation models for topical ocular drug administration.

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Topical ocular pharmacokinetics and bioavailability for a cocktail of atenolol, timolol and betaxolol in rabbits

Cited by 29 publications

References 19 publications

Comprehensive Ocular and Systemic Pharmacokinetics of Brinzolamide in Rabbits After Intracameral, Topical, and Intravenous Administration

Comprehensive Ocular and Systemic Pharmacokinetics of Brinzolamide in Rabbits After Intracameral, Topical, and Intravenous Administration

Topical ophthalmic administration: Can a drug instilled onto the ocular surface exert an effect at the back of the eye?

Partitioning and Spatial Distribution of Drugs in Ocular Surface Tissues

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