The Ocular Pharmacokinetics of Topical Diclofenac Is Affected by Ocular Inflammation

Abstract

The ocular pharmacokinetics of topical diclofenac sodium was studied in two experimental models of ocular inflammation and compared to physiological conditions. Keratitis or uveitis were induced by intrastromal injection of clove oil or by intravitreal lipopolysaccharide in rabbits. The control eyes were not inflamed. Simultaneously to the induction of inflammation, 30 µl of 0.1% diclofenac were applied topically in the right eye. Diclofenac levels were measured by HPLC in the cornea, aqueous humor (AH), iris/ciliary body (ICB) and plasma 30 min, 1, 3, 6 and 12 h after application. In physiological conditions, diclofenac reached a peak level in the cornea and ICB at 30 min slowly decreasing afterwards. Low levels of diclofenac were found in AH. In keratitic eyes, two peak levels which were significantly higher than in the controls were found in the cornea 30 min and 3 h after application. Diclofenac concentrations in keratitic AH and ICB were lower than in controls. In uveitic eyes, corneal and ICB levels peaked at 30 min, being significantly higher than in controls, and decreased quickly to very low levels at 1 h after application. In uveitic AH, diclofenac levels were lower than in controls. Plasma levels were very low (less than 0.1 µg/ml) in all experimental groups. It is concluded that the ocular pharmacokinetics of topical diclofenac is affected by inflammatory processes in the eye, reaching higher levels in the target tissues.

Bioavailability and biochemical effects of diclofenac sodium 0.1% ophthalmic solution in the domestic chicken (Gallus gallus domesticus)

“…If we assume 100% systemic absorption of the diclofenac sodium ophthalmic drops (~0.04 mg/drop), the mean per treatment dose of diclofenac for birds in the present study is approximately 0.028 mg/kg and 0.057 mg/kg for the treated groups 2 and 3, respectively. The extent of systemic absorption from topically applied ophthalmic diclofenac is unknown, however, given the low plasma concentration detected in the present and previous studies it is unlikely that a toxic level could be reached in plasma …”

“…Corticosteroids may also be used to treat ocular inflammation, however, topical corticosteroids are used cautiously in ophthalmic diseases due to potential side effects . In birds, topical ophthalmic corticosteroids use is further limited by systemic absorption and consequent potential immunosuppression .…”

“…Topical diclofenac sodium ophthalmic solution has been used in domestic and wild‐caught birds for treatment of ocular inflammation without reported negative clinical side effects . However, following topical ophthalmic application, medications are absorbed into systemic circulation, creating the potential for systemic side effects . To the authors' knowledge, no studies have evaluated the bioavailability or hemodynamics of the drug following topical ophthalmic administration in avian species.…”

Ocular Pharmacokinetics of Mapracorat, a Novel, Selective Glucocorticoid Receptor Agonist, in Rabbits and Monkeys

“…Taken together, the pharmacokinetic data and published pharmacology data suggest that any subtle differences between the ocular in vivo potency of mapracorat compared with that of traditional GCs are most likely related to its ocular pharmacokinetic properties. However, because ocular inflammation can potentially alter the pharmacokinetics of topically applied drugs (Barza, 1978;Palmero et al, 1999), additional pharmacokinetic studies in animals with ocular inflammation (ocular disease models) could be informative to more fully assess the TABLE 2 pharmacokinetic/pharmacodynamic relationship for mapracorat compared with that for traditional GCs. Exposure to mapracorat in various ocular tissues was investigated over an extremely large dose range of 0.01 to 3000 g/eye in rabbits and 50 to 3000 g/eye in monkeys.…”

Inhibition of COX in Ocular Tissues: AnIn VitroModel to Identify Selective COX-2 Inhibitors

“…Although the pharmacokinetics of the drug can influence its concentration within ocular tissues, and it is important to compare "in vitro" data with animal models of ocular inflammation as well as in humans (27,28), we suggest that this "in vitro" model could be used as a suitable assay system to determine the COX-2 selectivity of new NSAIDs during inflammatory events in ocular tissues.…”