Tear Fluid Pharmacokinetics Following Oral Prednisone Administration in Dogs With and Without Conjunctivitis

Abstract

Purpose: To describe the pharmacokinetics (PK) of prednisone and prednisolone in tear fluid of dogs receiving oral prednisone at anti-inflammatory to immunosuppressive doses and to assess the impact of induced conjunctivitis on lacrimal drug levels. Methods: Six healthy Beagle dogs were administered 4 courses of prednisone at 0.5, 1.0, 2.0, and 4.0 mg/kg given orally once a day for 5 days. At steady state, topical histamine was applied to induce mild (1 mg/mL) or severe (375 mg/mL) conjunctivitis in 1 eye of each dog and tear samples were collected from both eyes at selected times. Prednisone and prednisolone were quantified in tears by liquid chromatography-mass spectrometry. Results: Lacrimal prednisone and prednisolone concentrations ranged from 2 to 523 ng/mL and 5 to 191 ng/mL, respectively. Drug concentrations were overall greater in dogs receiving higher doses of prednisone, but were not correlated with tear flow rate. Eyes with conjunctivitis often had larger amounts of prednisone and prednisolone in tear fluid compared to control eyes (up to +64%), but differences were not statistically significant. Significantly greater, but clinically insignificant, levels of prednisolone were found in eyes with severe versus mild conjunctivitis for oral prednisone doses ≥1.0 mg/kg. Conclusions: Disruption of the blood–tear barrier with conjunctivitis did not significantly affect drug levels in tears. Based on drug PK in tears, oral prednisone is likely safe for the management of reflex uveitis and ocular surface diseases. However, further prospective trials using systemic corticotherapy in diseased animals are warranted to confirm findings from this preclinical study.

Impact of acute conjunctivitis on ocular surface homeostasis in dogs

“…Topical histamine provides a robust method to induce conjunctivitis in a rapid and minimally invasive manner in dogs 19,29 ; however, the duration of conjunctivitis is limited in time as the disease is self-resolving (average duration of 115 and 390 minutes with 1 and 375 mg/mL solutions, respectively). 19 One could consider repeating administration of topical histamine to prolong the duration of conjunctival swelling, as recently performed in a pharmacokinetic study of prednisone in dogs, 39 although the safety profile of consistent extended dosing with histamine is currently unknown. Nevertheless, the present study shows that experimentally induced conjunctivitis is enough to activate the lacrimal functional unit and cause reflex tearing, irrespective of noxious stimulation to the cornea.…”

An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface

“…Topically and systemically administered drugs can be quantified in tear fluid to determine the clinical efficacy and dosing frequency from fitting of kinetic data. [211][212][213][214][215] Multiple "omics" approaches can also be utilized for analysis of the tear fluid including proteomics, 173,190,191,[216][217][218][219][220] lipidomics, 141,206,221,222 and metabolomics, 222…”

“…41 cellulose filter paper and possess specific characteristics to promote tolerance (5-mm width × 35-mm length, 0.22-mm thick, 20-25 µm porosity, foldable extremity for ease of insertion). 249,257 In addition to their conventional use for aqueous tear assessment, Schirmer strips can retrieve tear fluid for bioanalytical purposes in humans, 182,216,219,220,228,231,258 dogs, 190,209,211,214,215,240,259 and small laboratory species. 244,260,261 For instance, Schirmer strips were used for indepth characterization of proteomics in human 173 and canine tears, 190 and can also successfully recover specific analytes such as cytokines, 200,258 clusterin, 182 and xenobiotics.…”

“…244,260,261 For instance, Schirmer strips were used for indepth characterization of proteomics in human 173 and canine tears, 190 and can also successfully recover specific analytes such as cytokines, 200,258 clusterin, 182 and xenobiotics. 211,[213][214][215]244,262 Absorbent sponges exist in different material types such as cellulose, 234,236,263,264 polyvinyl acetal, 209,214,228,236,244,264-266 polyester, 239,242,266 and polyrurethane. 236 A material with hydrophilic and hydrophobic properties (e.g., polyvinyl acetal and polyurethane) 236,264 is generally preferred to optimize the amount of fluid absorbed and the amount of fluid retrieved from the sponge.…”

“…244 On the other hand, the ability to control the volume of tears absorbed with Schirmer strips (i.e., same mm mark) generally improves the reproducibility of the results. 209,214,215,273 As such, the authors prefer (i) absorbent sponges for collecting large volumes of tears in canine subjects-that is, for further use as blank tears in bioanalytical assays, for example-and (ii) Schirmer strips for collecting known amounts of tears in any scenario where reproducibility of the data is important (i.e., for group comparisons, or follow-up of the same individual over time).…”