Pharmacokinetics of Ophthalmic Corticosteroids
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British Journal ofOphthalmology 1992; 76: 681-684 681 MINI REVIEW Br J Ophthalmol: first published as 10.1136/bjo.76.11.681 on 1 November 1992. Downloaded from Pharmacokinetics of ophthalmic corticosteroids Corticosteroids have been used by ophthalmologists with an identical vehicle, the aqueous humour concentrations of increasing frequency over the past 30 years, with the these steroids are almost identical.'9 None the less it is concomitant development of a diverse range of drop, essential when considering such empirical data, to recall that ointment, subconjunctival, and oral preparations. Though the systemic anti-inflammatory effect of both betamethasone the clinical benefits and side effects of such corticosteroid and dexamethasone is five to seven times that of predniso- preparations have been well documented, their basic lone.39"' The local anti-inflammatory potency of ocular pharmacokinetics in the human eye have yet to be fully steroids has yet to be fully investigated and whilst early work established. Indeed most of our pharmacokinetic knowledge suggested that prednisolone acetate 1% had the greatest anti- of these drugs has been elucidated by extrapolation of data inflammatory effect in experimental keratitis,'7 later studies obtained from rabbit experiments.1-26 These results can be demonstrated that fluorometholone acetate in a 1% formu- significantly disparate from human data because of the lation was equally efficacious in the same model.26 However, thinner rabbit cornea, lower rabbit blink rate, effect of prednisolone acetate 1 -0% drops have been shown to signific- general anaesthetic, upright or recumbent position, antly inhibit the tear film polymorphonuclear leucocyte vascularity ofthe rabbit orbital plexus, and small rabbit body response to partial denudation of the corneal epithelium, mass.'827-29 Thus, in general, measurements of steroid con- whereas 0 1% concentrations of prednisolone acetate, dexa- centration in rabbit eyes27 13 19-212425 tend to be significantly methasone, and fluorometholone are ineffective.3 As already higher than those recorded in humans.3135 noted, the absence of corneal epithelium can significantly affect the penetration of topical steroids, and it may also be relevant to the clinical situation that higher corneal concen- Topical ophthalmic drops/ointments trations of steroid may occur in the presence of intraocular These are still the most common methods of administering inflammation,9 whereas the concomitant application of an steroids to the eye and following a single topical drop, antibiotic drop within 60 seconds of steroid application can steroid is measurable in human aqueous humour within reduce the bioavailability of the applied steroid by almost 15-30 minutes.3132 Not surprisingly, increased steroid 70%.23 It has not been established which concentration of concentration in topical preparations generally results in steroid is desirable for minor ocular inflammatory conditions higher intraocular concentrations,'3 14 but for prednisolone such as postoperative uveitis, and whilst concentrations of acetate the optimum dose response effect in experimental 670 ng/ml of prednisolone have been recorded in human keratitis occurs at a 1% concentration, and is not improved aqueous humour,33 perhaps a peak of 25 ng/ml3' might by further increases in concentration.20 Increasing ocular be sufficient to suppress inflammation and minimise side http://bjo.bmj.com/ contact time by preparing topical steroids in a microsus- effects.4' For comparison, peak timolol concentrations of pension,25 gel, or viscous formulation3536 can double the 2500 ng/ml have been recorded in rabbit aqueous humour corneal and aqueous humour concentrations of steroid following topical application, yet [ receptor blockade can be compared with the same drug applied as a solution.'33536 obtained by as little as 9 ng/ml.42 Other apparently minor changes in formulation, such as Preparation of prednisolone acetate as a gel provides a the addition of benzalkonium, can significantly alter the more prolonged release43 and higher peak aqueous concen- pharmacokinetics of topical steroids.'3 For these reasons tration when compared with an equivalent topical solution.24 on September 25, 2021 by guest. Protected copyright. many workers chose to use commercially prepared 'off However, some viscous agents and ointments may actually the shelf' steroids in an attempt to unravel differences in produce lower peak ocular concentrations of steroid when pharmacokinetic behaviour, which may be associated with compared with drops.'243 Despite this, owing to prolonged clinical efficacy.'721261321 II37 In contradistinction, the prep- release, a single application of a steroid ointment such as aration of different topical steroid derivatives in an identical dexamethasone phosphate results in only 25% less overall base vehicle has demonstrated that the greatest barrier to absorption of steroid than a single drop of the same steroid. 2 intraocular penetration is the lipid rich corneal epithelium, It is generally believed that most ofthe topical and, indeed, which retards the ingress of polar, hydrophilic derivatives subconjunctival steroid (see below), enters the eye via the such as prednisolone phosphate,9 126 but is much less of a cornea, thus radiolabelled hydrocortisone produces only barrier to lipophilic derivatives such as the alcohol and 2 5% ofthe anticipated aqueous humour concentration when acetate forms of dexamethasone and prednisolone.'5 16202638 corneal penetration is prevented, compared with topical Interestingly, if this epithelial barrier is removed predni- application with free access to the cornea.44 However, for solone phosphate penetrates the cornea in much higher other drugs such as pilocarpine and timolol, penetration into quantities than the lipophilic, acetate derivative.'2 These the iris and ciliary body via the non-corneal route may additive effects of increased concentration, lipophilic deriv- account for drug concentrations which reach almost 10% of ation, and the increased contact time afforded by a micro- the combined corneal and non-corneal route," and such suspension have been demonstrated in humans, where a trans-scleral penetration may be even more important for single drop of prednisolone acetate 1-0% microsuspension larger molecules, such as inulin.4 has been shown to produce intraocular steroid concentrations which were 20-fold those of a single drop of prednisolone phosphate 0 5% solution,3133 and almost 100-fold those of a Periocular injections single drop of betamethasone phosphate 0*l% solution.32 In Repeated subconjunctival injections of prednisolone (50 mg) contrast, when dexamethasone, prednisolone, and fluoro- have been shown to be inferior to hourly topical prednisolone metholone are all formulated at a concentration of 0-1% in acetate 1% drops (6-5 mg) in reducing the inflammatory 682 McGhee response in experimental keratitis.2' Early analytical tech- tact lenses could be presoaked in a drug solution and used as niques suggested that such subconjunctivally injected steroid a form ofdelayed release vehicle.52 A few years later Hull et al Br J Ophthalmol: first published as 10.1136/bjo.76.11.681 on 1 November 1992. Downloaded from entered the eye via the sclera.5 Indeed, the sclera is readily established that hydrophilic contact lenses, presoaked in 1% permeable to even relatively large molecules such as prednisolone phosphate, produced an aqueous humour peak albumin,* and therefore, not surprisingly, high levels of concentration that was three to fourfold that obtained by corticosteroid can be detected in the sclera underlying a application of topical drops and this advantage was main- subconjunctival injection site.5 However, the greater con- tained at 4 hours.53 The search for a topically applied, centration of such steroid appears to enter the eye by slow release drug system in other areas led to the successful diffusing through the puncture site in the conjunctiva into development of pilocarpine ocuserts, which though not the tear film, and thence via the cornea into the intraocular widely used, and despite some limitations, have been shown milieu.'I4 to be a viable alternative to topical drops in certain patients.54 In this context it is not unexpected that sub-Tenon's Similarly, early soluble collagen inserts presoaked in injections of methyl prednisolone in monkeys produced gentamicin produced higher tear film and corneal concentra- significant anterior segment steroid concentrations (approx tions of gentamicin than gentamicin administered in drop, 25 ng/ml) but could only produce peak vitreous concen- ointment, or subconjunctival form.55 The development of trations of 2 ng/ml.47 In contrast, retrobulbar methyl dissolving collagen shields has rekindled interest in this prednisolone in the same model produced much higher method of delivering ophthalmic drugs and such shields posterior uveal/retinal concentrations and significant presoaked in tobramycin have been well tolerated by vitreous levels which persisted for up to 9 days.48 These patients56 and have been shown to produce higher aqueous discrepancies might be partly explained by the lack of post- and corneal concentrations of tobramycin than subcon- equatorial diffusion of drug following subconjunctival and junctival injections.57 Collagen shields have also been sug- sub-Tenon's injections.29 It is notable that, in contrast to gested as the optimum vehicle for poorly soluble drugs such the enhanced corneal penetration of topical