Ocular pharmacokinetics of atenolol, timolol and betaxolol cocktail: Tissue exposures in the rabbit eye

Fayyaz, Anam; Vellonen, Kati‐Sisko; Ranta, Veli‐Pekka; Toropainen, Elisa; Reinisalo, Mika; Valtari, Annika; Puranen, Jooseppi; Ricci, Giuseppe D’Amico; Heikkinen, Emma M.; Gardner, Iain; Ruponen, Marika; Urtti, Arto; Jamei, Masoud; Amo, Eva M. del

doi:10.1016/j.ejpb.2021.06.003

Cited by 21 publications

(19 citation statements)

References 28 publications

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“…The drug can also back-diffuse from aqueous humor into the cornea (Araie et al, 1982;Acheampong et al, 1995a;Fayyaz et al, 2020b). This has been observed for lipophilic drugs, when the drug exposure (area under the curve of the concentration-time profile, AUC) was measured in the corneal epithelium for three topical beta-blockers in the rabbit eye, and the most lipophilic drug, betaxolol, had a seven times higher AUC 0 to ∞ than the more hydrophilic compound, atenolol (Fayyaz et al, 2021). In addition, some fraction of the drug in the cornea may diffuse laterally to the sclera.…”

Section: Corneal Absorption Routementioning

confidence: 93%

“…Even though drug distribution from the aqueous humor into the vitreous has been proposed after topical administration (Boddu et al, 2014;Sripetch and Loftsson, 2021;Löscher et al, 2022), this path seems unlikely. Drug diffusion from the Frontiers in Drug Delivery frontiersin.org aqueous humor through the pupil into the posterior chamber would be in the opposite direction to the aqueous humor flow, and the lens further acts as a barrier, limiting the drug's circulation (Schoenwald et al, 1997;Fayyaz et al, 2021). Moreover, the drug lenticular distribution is observed only in the outermost lens layers capsule, epithelium (only present anteriorly), and the external cortex fibers (Heikkinen et al, 2018).…”

Section: Corneal Absorption Routementioning

confidence: 99%

“…Topically applied ophthalmic drugs may be absorbed via the non-corneal absorption route crossing the bulbar conjunctiva and the anterior sclera into the uveal tract, with the drug reaching the iris-ciliary body bypassing the aqueous humor (Ahmed and Patton, 1985; (Figure 4). This route is important for drugs with poor permeation across the cornea, such as hydrophilic drugs (Fayyaz et al, 2021) and large molecules such as inulin (5 kDa, ~1.2 nm) (Ahmed and Patton, 1985;.…”

Section: Non-corneal Absorption Routementioning

confidence: 99%

“…However, this makes it difficult to conclude the real drug exposure exclusively in the neural retina. In several extensive studies on ocular distribution after topical drug solution instillation, choroid-retina concentrations have been typically measured (Araie et al, 1982;Acheampong et al, 1995b;Acheampong et al, 2002) or alternatively only vitreous concentrations have been analyzed from the posterior segment (Urtti et al, 1990;Fayyaz et al, 2021).…”

Section: Further Insidementioning

confidence: 99%

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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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Section: Corneal Absorption Routementioning

confidence: 93%

Section: Corneal Absorption Routementioning

confidence: 99%

Section: Non-corneal Absorption Routementioning

confidence: 99%

Section: Further Insidementioning

confidence: 99%

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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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“…The topical route is preferred for management of anterior segment diseases, due to their low cost, ease of administration, and patient compliance [19,20]. However, this route is not able to deliver the drug to the posterior segment due to the anatomical and physiological barriers of the eye.…”

Section: Topical Routementioning

confidence: 99%

Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems

et al. 2021

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One of the major impediments to drug development is low aqueous solubility and thus poor bioavailability, which leads to insufficient clinical utility. Around 70–80% of drugs in the discovery pipeline are suffering from poor aqueous solubility and poor bioavailability, which is a major challenge when one has to develop an ocular drug delivery system. The outer lipid layer, pre-corneal, dynamic, and static ocular barriers limit drug availability to the targeted ocular tissues. Biopharmaceutical Classification System (BCS) class II drugs with adequate permeability and limited or no aqueous solubility have been extensively studied for various polymer-based solubility enhancement approaches. The hydrophilic nature of cellulosic polymers and their tunable properties make them the polymers of choice in various solubility-enhancement techniques. This review focuses on various cellulose derivatives, specifically, their role, current status and novel modified cellulosic polymers for enhancing the bioavailability of BCS class II drugs in ocular drug delivery systems.

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Mass spectrometry in ocular drug research

del Amo,

Vellonen,

Urtti

et al. 2023

Mass Spectrometry Reviews

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Mass spectrometry (MS) has been proven as an excellent tool in ocular drug research allowing analyzes from small samples and low concentrations. This review begins with a short introduction to eye physiology and ocular pharmacokinetics and the relevance of advancing ophthalmic treatments. The second part of the review consists of an introduction to ocular proteomics, with special emphasis on targeted absolute quantitation of membrane transporters and metabolizing enzymes. The third part of the review deals with liquid chromatography–MS (LC‐MS) and MS imaging (MSI) methods used in the analysis of drugs and metabolites in ocular samples. The sensitivity and speed of LC‐MS make simultaneous quantitation of various drugs and metabolites possible in minute tissue samples, even though ocular sample preparation requires careful handling. The MSI methodology is on the verge of becoming as important as LC‐MS in ocular pharmacokinetic studies, since the spatial resolution has reached the level, where cell layers can be separated, and quantitation with isotope‐labeled standards has come more reliable. MS will remain in the foreseeable future as the main analytical method that will progress our understanding of ocular pharmacokinetics.

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Ocular pharmacokinetics of atenolol, timolol and betaxolol cocktail: Tissue exposures in the rabbit eye

Cited by 21 publications

References 28 publications

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

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

Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems

Mass spectrometry in ocular drug research

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