Topical steroids in ophthalmology. Part 1. Pharmacokinetics

Topical glucocorticoids remain the cornerstone of therapy for inflammatory disorders of the anterior segment of the eye; nevertheless, their clinical efficacy exhibits considerable variability. This heterogeneity is rooted in the distinct pharmacological profiles of individual steroids, which directly govern their capacity for ocular penetration and tissue accumulation. The review offers a comprehensive analysis of the pharmacokinetics of key ophthalmic steroids — prednisolone, dexamethasone, fluorometholone, hydrocortisone, loteprednol, and difluprednate. The principal determinants of corneal penetration are examined in detail, including the physicochemical properties of the molecule (lipophilicity, solubility, molecular size), formulation characteristics, the condition of the ocular surface, and the route of administration. Emphasis is placed on a comparative assessment of aqueous humor concentrations, which serve as a key integrative indicator of intraocular bioavailability. The analysis demonstrates considerable heterogeneity in pharmacokinetic profiles — a finding of direct clinical relevance. Furthermore, the relationship between the physicochemical properties of these steroids, their relative anti-inflammatory potency, and anticipated clinical outcomes are discussed. The data presented herein provide a scientific foundation for the rational selection of a therapeutic agent, ensuring that the desired clinical result is achieved in consideration of the specific pharmacokinetic properties of each drug, as well as the nature and localization of the inflammatory process.

1. Sherif Z, Pleyer U. Corticosteroids in ophthalmology: past-present-future. Ophthalmologica. 2002; 216 (5): 305–15. doi: 10.1159/000066189

2. Gaballa SA, Kompella UB, Elgarhy O, et al. Corticosteroids in ophthalmology: drug delivery innovations, pharmacology, clinical applications, and future perspectives. Drug Deliv Transl Res. 2021; 11 (3): 866–93. doi: 10.1007/s13346-020-00843-z

3. Elkinton JR, Hunt ADJr. Effects of pituitary adrenocorticotropic hormone therapy. J Am Med Assoc. 1949; 141 (18): 1273–9. doi: 10.1001/jama.1949.02910180001001

4. Fung AT, Tran T, Lim LL, et al. Local delivery of corticosteroids in clinical ophthalmology: a review. Clin Exp Ophthalmol. 2020; 48 (3): 366–401. doi: 10.1111/ceo.13702

5. Ramamoorthy S, Cidlowski JA. Corticosteroids: mechanisms of action in health and disease. Rheum Dis Clin North Am. 2016; 42 (1): 15-vii. doi: 10.1016/j.rdc.2015.08.002

6. Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov. 2012; 7 (10): 863–75. doi: 10.1517/17460441.2012.714363

7. McGhee CN, Watson DG, Midgley JM, et al. Penetration of synthetic corticosteroids into human aqueous humour. Eye (Lond). 1990; 4 (Pt 3): 526–30. doi:10.1038/eye.1990.70

8. Awan MA, Agarwal PK, Watson DG, et al. Penetration of topical and subconjunctival corticosteroids into human aqueous humour and its therapeutic significance. Br J Ophthalmol. 2009; 93 (6): 708–13. doi: 10.1136/bjo.2008.154906

9. McGhee CN. Pharmacokinetics of ophthalmic corticosteroids. Br J Ophthalmol. 1992; 76 (11): 681–4. doi:10.1136/bjo.76.11.681

10. McGhee CN, Noble MJ, Watson DG, et al. Penetration of topically applied prednisolone sodium phosphate into human aqueous humour. Eye (Lond). 1989; 3 (Pt 4): 463–7. doi: 10.1038/eye.1989.69

11. Hull DS, Hine JE, Edelhauser JF, Hyndiuk RA. Permeability of the isolated rabbit cornea to corticosteroids. Invest Ophthalmol. 1974 Jun; 13 (6): 457–9. PMID: 4831698.

12. Kupferman A, Pratt MV, Suckewer K, Leibowitz HM. Topically applied steroids in corneal disease. 3. The role of drug derivative in stromal absorption of dexamethasone. Arch Ophthalmol. 1974; 91 (5): 373–6. doi: 10.1001/archopht.1974.03900060385008

13. Sieg JW, Robinson JR. Vehicle effects on ocular drug bioavailability i: evaluation of fluorometholone. J Pharm Sci. 1975; 64 (6): 931–6. doi: 10.1002/jps.2600640606

14. Schoenwald RD, Harris RG, Turner D, Knowles W, Chien DS. Ophthalmic bioequivalence of steroid/antibiotic combination formulations. Biopharm Drug Dispos. 1987; 8 (6): 527-48. doi: 10.1002/bdd.2510080605

15. Thakur A, Kadam RS, Kompella UB. Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids. Drug Metab Dispos. 2011; 39 (5): 771-81. doi: 10.1124/dmd.110.037408

16. Athanasiadis Y, Tsatsos M, Sharma A, Hossain P. Subconjunctival triamcinolone acetonide in the management of ocular inflammatory disease. J Ocul Pharmacol Ther. 2013; 29 (6): 516-22. doi: 10.1089/jop.2012.0208

17. Schopf L, Enlow E, Popov A, et al. Ocular pharmacokinetics of a novel loteprednol etabonate 0.4% ophthalmic formulation. Ophthalmol Ther. 2014; 3 (1-2): 63-72. doi: 10.1007/s40123-014-0021-z

18. Mercado-Sesma A, Contreras-Rubio A, Baiza-Duran L, et al. Bioavailability of generic 0.05 % difluprednate emulsion in the aqueous humor, cornea, and conjunctiva of New Zealand rabbits after a single dose compared with commercial difluprednate. J Ophthalmic Inflamm Infect. 2017; 7 (1): 10. doi: 10.1186/s12348-017-0127-2

19. Naageshwaran V, Ranta VP, Toropainen E, et al. Topical pharmacokinetics of dexamethasone suspensions in the rabbit eye: bioavailability comparison. Int J Pharm. 2022; 615: 121515. doi: 10.1016/j.ijpharm.2022.121515

20. Grass GM, Robinson JR. Mechanisms of corneal drug penetration. I: in vivo and in vitro kinetics. J Pharm Sci. 1988; 77 (1): 3-14. doi: 10.1002/jps.2600770103

21. Baba K, Hashida N, Tujikawa M, et al. The generation of fluorometholone nanocrystal eye drops, their metabolization to dihydrofluorometholone and penetration into rabbit eyes. Int J Pharm. 2021; 592: 120067. doi: 10.1016/j.ijpharm.2020.120067

22. Schoenwald RD, Stewart P. Effect of particle size on ophthalmic bioavailability of dexamethasone suspensions in rabbits. J Pharm Sci. 1980; 69 (4): 391-4. doi: 10.1002/jps.2600690407

23. Kupferman A, Leibowitz HM. Topically applied steroids in corneal disease. IV. The role of drug concentration in stromal absorption of prednisolone acetate. Arch Ophthalmol. 1974; 91(5): 377-80. doi: 10.1001/archopht.1974.03900060389009

24. Cagini C, Cometa F, Torroni G, et al. Dexamethasone disodium phosphate penetration into the human aqueous humor after topical application. Curr Eye Res. 2016; 41 (7): 897-9. doi: 10.3109/02713683.2015.1083589

25. Balla A, Ruponen M, Valtari A, et al. Understanding dexamethasone kinetics in the rabbit tear fluid: drug release and clearance from solution, suspension and hydrogel formulations. Eur J Pharm Biopharm. 2022; 172: 53-60. doi: 10.1016/j.ejpb.2022.01.005

26. Dang DH, Riaz KM, Karamichos D. Treatment of non-Infectious corneal injury: review of diagnostic agents, therapeutic medications, and future targets. Drugs. 2022; 82 (2): 145-67. doi: 10.1007/s40265-021-01660-5

27. Marlowe ZT, Davio SR. Dose uniformity of loteprednol etabonate ophthalmic gel (0.5 %) compared with branded and generic prednisolone acetate ophthalmic suspension (1 %). Clin Ophthalmol. 2014; 8: 23-9. doi: 10.2147/OPTH.S55004

28. Leibowitz HM, Kupferman A. Drug interaction in the eye. Concurrent corticosteroid-antibiotic therapy for inflammatory keratitis. Arch Ophthalmol. 1977; 95 (4): 682-5. doi: 10.1001/archopht.1977.04450040148023

29. Lee H, Kim SM, Rahaman MI, et al. Corticosteroid-antibiotic interactions in bacteria that cause corneal infection. Transl Vis Sci Technol. 2023; 12 (5): 16. doi: 10.1167/tvst.12.5.16

30. Weijtens O, Schoemaker RC, Romijn FP, et al. Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate. Ophthalmology. 2002; 109 (10): 1887-91. doi: 10.1016/s0161-6420(02)01176-4

31. Weijtens O, Feron EJ, Schoemaker RC, et al. High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection. Am J Ophthalmol. 1999; 128 (2): 192-7. doi: 10.1016/s0002-9394(99)00129-4

32. Weijtens O, van der Sluijs FA, Schoemaker RC, et al. Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection. Am J Ophthalmol. 1997; 123 (3): 358-63. doi: 10.1016/s0002-9394(14)70131-x

33. Watson DG, McGhee CN, Midgley JM, Dutton GN, Noble MJ. Penetration of topically applied betamethasone sodium phosphate into human aqueous humour. Eye (Lond). 1990; 4 (Pt 4): 603-6. doi: 10.1038/eye.1990.84

34. Watson D, Noble MJ, Dutton GN, et al. Penetration of topically applied dexamethasone alcohol into human aqueous humor. Arch Ophthalmol. 1988; 106 (5): 686-7. doi: 10.1001/archopht.1988.01060130748037

35. Kristinsson JK, Fridriksdottir H, Thorisdottir S, et al. Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Aqueous humor pharmacokinetics in humans. Invest Ophthalmol Vis Sci. 1996 May; 37 (6): 1199-203. PMID: 8631635.

36. Leibowitz HM, Berrospi AR, Kupferman A, et al. Penetration of topically administered prednisolone acetate into the human aqueous humor. Am J Ophthalmol. 1977; 83 (3): 402-6. doi: 10.1016/0002-9394(77)90740-1

37. Debnath SC, Richards AB. Concentration of clobetasone butyrate in aqueous humour. Br J Ophthalmol. 1983; 67 (3): 203-5. doi: 10.1136/bjo.67.3.203

38. Druzgala P, Wu WM, Bodor N. Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res. 1991; 10 (10): 933-7. doi: 10.3109/02713689109020329

39. Cagini C, Muzi A, Castellucci G, et al. Kinetics of hydrocortisone sodium phosphate penetration into the human aqueous humor after topical application. Int J Clin Pract. 2021; 75 (12):e14987. doi: 10.1111/ijcp.14987

40. Masoumpour MB, Nowroozzadeh MH, Razeghinejad MR. Current and future techniques in wound healing modulation after glaucoma filtering surgeries. Open Ophthalmol J. 2016 Feb 29; 10: 68-85. doi: 10.2174/1874364101610010068

41. Jermak CM, Dellacroce JT, Heffez J, Peyman GA. Triamcinolone acetonide in ocular therapeutics. Surv Ophthalmol. 2007; 52 (5): 503-22. doi: 10.1016/j.survophthal.2007.06.004

42. Razeghinejad MR, Katz LJ. Steroid-induced iatrogenic glaucoma. Ophthalmic Res. 2012; 47 (2): 66-80. doi:10.1159/000328630