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.

Keywords: blood–tear barrier; canine; pharmacokinetics; prednisolone; prednisone; tear film.

FIG. 1.

Topical histamine rapidly induced conjunctivitis (<1 min) that was either mild [(A); 1.0 mg/mL solution] or severe [(B); 375 mg/mL solution]. Color images are available online.

FIG. 2.

Tear film concentrations (mean + standard deviation) of prednisone (A, B) and prednisolone (C, D) in dogs receiving oral prednisone at 0.5 mg/kg once daily (black line, circles), 1.0 mg/kg once daily (red lines, down triangles), 2.0 mg/kg once daily (green lines, squares), and 4.0 mg/kg once daily (blue lines, up triangles). The concentrations are depicted for control eyes (A, C) and eyes with experimentally induced conjunctivitis (B, D). Of note, the conjunctivitis group includes eyes with mild and severe conjunctivitis. Color images are available online.

FIG. 3.

Box-and-whiskers plots depicting the area under the tear concentration–time curve from time zero to time of last measurable concentration (AUC_last). Each plot depicts the mean (dotted line), median (solid line), 2.5th percentile (lower whisker), 25th percentile (lower limit of box), 75th percentile (upper limit of box), and 97.5th percentile (upper whisker). Data for prednisone (A) and prednisolone (B) are shown for all 4 oral doses of prednisone (0.5–4.0 mg/kg) in both control eyes (white boxes) and eyes with experimentally induced conjunctivitis (dark gray). Of note, the conjunctivitis group includes eyes with mild and severe conjunctivitis. Within the same drug dose, comparisons between control and conjunctivitis eyes (t test) are described with P values above the plots. Within the same ocular group (control or conjunctivitis), differences among doses (one-way analysis of variance) are depicted with symbols to demonstrate statistically greater AUC_last compared to dose 1 (#), dose 2 (†), and dose 3 (‡).

FIG. 4.

Bar charts depicting mean + standard deviation of area under the tear concentration-time curve from time zero to time of last measurable concentration (AUC_last). Data for tear concentrations of prednisone (A) and prednisolone (B) are shown for all 4 oral doses of prednisone (0.5–4.0 mg/kg) in eyes with experimentally induced mild conjunctivitis (light gray) or severe conjunctivitis (dark gray). Within the same dose, statistical comparisons between mild and severe conjunctivitis (t test) are described with P values above the plots, and statistical significance (P < 0.05) is depicted with an asterisk (*).