Ocular metabolism and distribution of drugs in the rabbit eye: Quantitative assessment after intracameral and intravitreal administrations

Amo, Eva M. del; Hammid, Anam; Tausch, Melanie; Toropainen, Elisa; Sadeghi, Hojjat; Valtari, Annika; Puranen, Jooseppi; Reinisalo, Mika; Ruponen, Marika; Urtti, Arto; Sauer, Achim; Honkakoski, Paavo

doi:10.1016/j.ijpharm.2021.121361

Cited by 22 publications

(22 citation statements)

References 39 publications

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“…From rabbit studies, among all drugs shown in Table 1, the highest measured concentration in the neural retina was obtained for dorzolamide, 2.8 µM (0.9 μg/ml) after instillation of the highest dose (3 µmol) (Sigurdsson et al, 2005). Drug retinal concentrations were higher than the vitreal ones for the same drug, and a similar trend can be seen after intracameral pharmacokinetic studies (del Amo et al, 2022), supporting the idea of drug penetration from the non-corneal route probably from the retina to the vitreal cavity.…”

Section: Further Insidementioning

confidence: 56%

“…After intracameral injection, the same kinetic pathways shown in Figure 3 are present with the obvious exclusion of pathway 1 (corneal absorption). Intracameral lipophilic drugs also have to undergo corneal partitioning (Naageshwaran et al, 2022;del Amo et al, 2022), while lens partitioning is less relevant (del Amo et al, 2022), for example, the AUC 0-5h cornea/ aqueous humor for acetaminophen was five times and for brimonidine seven times the corresponding AUC 0-5h lens/ aqueous humor. Interestingly, the same drugs injected in the vitreous humor (using a dose to acquire similar initial concentrations) achieved three times higher lens partitioning than after intracameral administration (del Amo et al, 2022), showing that lens access is more favorable from the vitreous than from the anterior chamber.…”

Section: Corneal Absorption Routementioning

confidence: 99%

“…Frontiers in Drug Delivery frontiersin.org 07 del Amo 10.3389/fddev.2022.954771 sunitinib) in six different ocular tissues (del Amo et al, 2022); metabolism was relevant only for those drugs that were a substrate of esterases (cefuroxime axetil), while enzymatic activity for those drugs metabolized by sulfotransferase (acetaminophen), aldehyde oxidase (brimonidine), or CYP3A (sunitinib) was found to be very low. In fact, the metabolite exposure in most ocular tissues was 12-10 3 times smaller than the exposure to the parent drug, so the impact of metabolism on drug clearance from the eye could be considered negligible (del Amo et al, 2022).…”

Section: Further Insidementioning

confidence: 99%

“…Only the free drug will exert an effect, and this is especially important for drugs that bind to melanin (Acheampong et al, 2002;Rimpelä et al, 2018a) or to other ocular sites, e.g., sunitinib. Not only is sunitinib a high melanin binder, but it also underwent high ocular partition to several ocular sites in albino rabbit pharmacokinetic studies e.g., to the cornea, iris-ciliary body, and retina after intracameral and intravitreal injections (del Amo et al, 2022).…”

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: Further Insidementioning

confidence: 56%

Section: Corneal Absorption Routementioning

confidence: 99%

Section: Further Insidementioning

confidence: 99%

Section: Further Insidementioning

confidence: 99%

See 2 more Smart Citations

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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“…Moreover, ocular tissues display variable esterase-mediated activities: hydrolysis of pilocarpine to pilocarpic acid occurs in the iris-ciliary body, retina, and choroid (Ellis et al, 1972), and bimatoprost free acid is formed in the rabbit and human cornea, sclera, and iris-ciliary body (Davies et al, 2003;Hellberg et al, 2003). We found that hydrolysis of cefuroxime axetil was high in the rabbit cornea, aqueous humor, and iris-ciliary body (del Amo et al, 2022).…”

Section: Introductionmentioning

confidence: 80%

Activity and Expression of Carboxylesterases and Arylacetamide Deacetylase in Human Ocular Tissues

et al. 2022

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As a multi-tissue organ, the eye possesses unique anatomy and physiology including differential expression of drug-metabolizing enzymes. Several hydrolytic enzymes, that play a major role in drug metabolism and bioactivation of prodrugs, have been detected in ocular tissues but data on their quantitative expression is scarce. Also, many ophthalmic drugs are prone to hydrolysis. Metabolic characterization of individual ocular tissues is useful for the drug development process, and therefore, seven individual ocular tissues from human eyes were analyzed for the activity and expression of carboxylesterases (CESs) and arylacetamide deacetylase (AADAC). Generic and selective human esterase substrates 4-nitrophenyl acetate (most esterases), D-luciferin methyl ester (CES1), fluorescein diacetate and procaine (CES2), and phenacetin (AADAC) were applied to determine the enzymes' specific activities.Enzyme kinetics and inhibition studies were performed with isoform-selective inhibitors digitonin (CES1) and verapamil and diltiazem (CES2). Enzyme contents were determined using quantitative targeted proteomics, and CES2 expression was confirmed by Western blotting. The expression and activity of human CES1 among ocular tissues varied by >10fold, with the highest levels found in the retina and iris-ciliary body. In contrast, human CES2 expression appeared lower and more similar between tissues whereas AADAC could not be detected. Inhibition studies showed that hydrolysis of fluorescein diacetate is also catalyzed by enzymes other than CES2. This study provides, for the first time, quantitative information on the tissue-dependent expression of human ocular esterases which can be useful for the development of ocular drugs, prodrugs, and in pharmacokinetic modeling of the eye.

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A Dual‐Drug Nanohybrid System Incorporating Nimodipine and Brain‐Derived Neurotrophic Factor Promotes Retinal Ganglion Cells Survival

Shen

Zhang

Wang

et al. 2023

Advanced Therapeutics

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Glaucoma, a leading cause of irreversible visual impairments and even blindness, is characterized by elevated intraocular pressure and progressive loss of structure and function of neuronal systems. To effectively protect neuronal systems from damage caused by elevated intraocular pressure, a novel dual‐drug nanohybrid has been developed by incorporating brain‐derived neurotrophic factor (BDNF)‐loaded mesoporous silica nanoparticles (BDNF@MSN) into the thermogel matrix with nimodipine (NMD) (BDNF@MSN‐NMD@Thermogel). The carrier materials (i.e., silica and thermogel) in this nanohybrid do not show any cytotoxicity to human lens epithelial cells and rat retinal precursor cells. This nanohybrid regulates the in vitro release of BDNF and NMD in a sustainable way for weeks. In optic nerve crush rodent models, a single intravitreal injection of BDNF@MSN‐NMD@Thermogel inhibits retinal neuroinflammation, significantly promotes retinal ganglion cells survival and restores visual function for nearly three months. This nanohybrid is thus a promising alternative for effective neuroprotection treatment for neuroinflammation‐related neurodegenerative diseases.

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Ocular metabolism and distribution of drugs in the rabbit eye: Quantitative assessment after intracameral and intravitreal administrations

Cited by 22 publications

References 39 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?

Activity and Expression of Carboxylesterases and Arylacetamide Deacetylase in Human Ocular Tissues

A Dual‐Drug Nanohybrid System Incorporating Nimodipine and Brain‐Derived Neurotrophic Factor Promotes Retinal Ganglion Cells Survival

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