Ocular Pharmacokinetics

Topical Ocular Instillation

The general process of ocular absorption from an eyedrop is surprisingly complex considering the simplicity of the administration method. Transcorneal absorption involves a series of events, including drug instillation, dilution in tear fluid, diffusion through the tear mucin layer, corneal penetration (epithelium, stroma, and endothelium), and transfer from cornea to aqueous humor. Parallel absorption via the conjunctiva/sclera also occurs; however, for the majority of drugs, this pathway is minor compared with the transcorneal route. In addition, nonproductive, competing pathways (e.g., nasolacrimal drainage or systemic absorption via the conjunctiva) operate to clear drug from the eye, thereby narrowing the time window during which absorption occurs (normally around 5-10 minutes).

Corneal Penetration

Transcorneal drug absorption is highly dependent on a drug's physicochemical properties, including its partition coefficient, molecular weight, solubility, and state of ionization. For most ophthalmic drugs, which are water soluble, the layers of stratified epithelial cells present the greatest barrier to penetration. The influence of the corneal epithelium on ocular absorption is clearly demonstrated by studying corneal penetration following removal of the epithelium. For rabbits administered topical ocular 14C-dexamethasone, radioactivity is detected in the cornea and aqueous humor only after removal of the corneal epithelium (24,25). Stroma and endothelium offer resistance only to highly lipophilic drugs. Penetration through the lipophilic epithelium and hydrophilic stroma exhibits a parabolic relationship between log corneal permeability coefficients and log octanol-water coefficients (26,27), with an optimal log octanol-water coefficient of 2.9. Huang et al. refined the parabolic model by demonstrating in vitro a sigmoidal relationship between permeability coefficient and partition coefficient (25, p. 308).

A drug's transport and distribution can be influenced by the dosage form, such as solution versus suspension, and by its pH, buffering capacity, viscosity, or presence of a penetration enhancer. Burstein and Anderson evaluated the effects of preservatives, vehicles, adjunct agents, and anatomy, and developed model systems for selecting the best formulations for preclinical evaluation and clinical use (15). For example, by adjusting pH so that the drug is mostly unionized, corneal penetration was greatly enhanced. Conversely, buffering that increases the portion of drug ionized can be expected to reduce the portion absorbed.

Some excipients, such as the preservative benzalkonium chloride (BAC), can also act as penetration enhancers. Madhu et al. studied the influence of BAC/EDTA (disodium edetate) on ocular bioavailability of ketorolac tromethamine following topical ocular instillation onto normal and de-epithelialized rabbit corneas in vitro and in vivo (28), demonstrating its ability to disrupt epithelial cell tight junctions, and so enhance penetration.

Noncorneal, "Productive" Ocular Absorption

Ahmed and Patton investigated corneal versus noncorneal penetration of topically applied drugs in the eye (29,30), and identified a "productive" noncorneal route with penetration through the conjunctiva and underlying sclera. This pathway, previously thought only to eliminate drug from the eye ("nonproductive" absorption), parallels the corneal route and may be particularly important for drugs with low corneal permeability, such as inulin. Moreover, this pathway, which bypasses the anterior chamber, can distribute drug to the uveal tract and vitreous humor.

Evaluating drug diffusion employing in vitro barrier models of the conjunctiva, sclera, and cornea, Ahmed et al. demonstrated higher permeability in sclera and conjunctiva than cornea (31). Permeability coefficients of evaluated P-blockers ranked as follows: propranolol > penbutolol > timolol > nadolol for cornea, and penbutolol > propranolol > timolol > nadolol for the sclera. Permeability was higher in cornea versus conjunctiva for inulin, but similar in the case of timolol. Similarly, Chien et al. studied the ocular penetration pathways of three a2-adrenergic agents in rabbits both in vitro and in vivo (32). The predominant pathway for absorption was the corneal route, with the exception of /j-aminoclonidine, the least lipophilic, which followed the conjunctival/ scleral route. The results suggest that the absorption pathway may be determined in part by lipophilicity and that hydrophilic compounds may prefer the conjunctival/scleral route.

In a study by Schoenwald et al., the conjunctival/scleral pathway yielded higher iris-ciliary body concentrations for all compounds evaluated with the exception of lipophilic rhodamine B (33). Romanelli et al. demonstrated the absorption of topical ocular bendazac into the retina-choroid via the conjunctival-scleral pathway (34). Noncorneal absorption was influenced more by physicochemical properties of the drug than characteristics of the formulation, whereas conversely transcorneal absorption could be influenced more by characteristics of the formulation.

Noncorneal, Nonproductive Absorption and Precorneal Drainage

Routes of absorption that lead to the removal of drug from the precorneal area, and do not result in direct ocular uptake, are referred to as nonproductive. These noncorneal pathways, which are in parallel with corneal absorption and include conjunctival uptake and drainage via the nasolacrimal duct, lead to systemic absorption by way of conjunctival blood vessels in the former case and removal through the nasal mucosa and gastrointestinal tract in the latter. As discussed, drug can penetrate the conjunctiva, and, via the sclera, enter the eye; however, blood vessels within the conjunctiva can also lead to systemic absorption.

Nonproductive, noncorneal absorption and drainage greatly impact precorneal residence time, and thereby ocular absorption. Drainage, in particular, is generally rapid and limits ocular contact at the site of absorption to 3 to 10 minutes (21). For most drugs, however, the lag time for drug to traverse the cornea and appear in the aqueous humor extends exposure to maximal concentration in the aqueous to between 20 and 60 minutes. Interestingly, rapid loss of drug from the precorneal region results in ocular absorption of less than 10%, and more typically, less than 1% to 2% of a topical dose. Therefore, conventionally most of the topical dose is unavailable for local efficacy, with greater than 90% absorbed into the systemic circulation. As an example, Ling et al. demonstrated ocular bioavailability of topical ocular ketorolac in anesthetized rabbits to be 4% and systemic absorption to be nearly complete (35). Tang-Liu et al., for topical ocular administration of levobunolol in rabbits, found that ocular bioavailability was only 2.5% while systemic bioavailability reached 46% (36).

A number of factors can influence drainage and noncorneal absorption, and include, for example, anesthesia, instillation volume, formulation viscosity, and the status of the nasolacrimal duct. Using a radioisotopic method, Chrai et al. evaluated the effect of instilled volume on drainage loss using miosis data in albino rabbits (37) and showed that unanesthetized rabbits had lacrimal volume of 7.5 |iL, whereas anesthetized rabbits had a slightly larger volume of 12.0 |iL. Moreover, lacrimal turnover was slower in anesthetized rabbits. In a separate study, using 99mTc (technetium), Chrai et al. demonstrated that drug loss through drainage increased with drop volume (38), and five-minute spacing between drops was optimal for minimizing loss attributable to drainage. A volume of no more than 5 to 10 |iL, containing a larger concentration of drug, was recommended, with at least a five-minute time gap between drops. By contrast, most commercial ophthalmic droppers deliver 30 to 70 |iL. Also, for two drugs given as two separate drops, the second drop will negatively influence the first, arguing for combination therapy. Significantly, Keister et al. showed that for drugs with high corneal permeability, ocular bioavailability is relatively unaffected by drug volume (39).

Viscosity is another factor that can regulate nonproductive absorption, as well as ocular absorption. Increasing vehicle viscosity may decrease drainage rate, prolong precorneal residence time, and increase ocular absorption. However, there appears to be a finite limit to the extent of the influence of viscosity. Zaki et al. using y-scintigraphy studied precorneal drainage with formulations containing radiolabeled polymers, either polyvinyl alcohol or hydroxymethylcellulose, in both rabbit and human (40). Significant retardation of drainage in humans was observed at higher polymer concentrations. Patton and Robinson also used polyvinyl alcohol, along with methylcellulose, to evaluate the relationship between viscosity and contact time or loss attributable to drainage (41). The optimum viscosity for rabbits ranged from 12 to 15 cP (centipoise). The relationship, however, was not proportional, and this was presumed to be related to increased shear forces from solutions of higher viscoelasticity. Chrai and Robinson also demonstrated, using methylcellulose vehicle, that increasing viscosity of an ophthalmic solution results in decreased drainage, and over the range of 1 to 15 cP, there was a threefold change in drainage rate constant and another threefold change over the range of 15 to 100 cP (42).

Occlusion of the nasolacrimal duct also is a means of controlling tear drainage and prolonging residence time. This highly effective means of increasing ocular bioavailability and concurrently decreasing systemic exposure, however, is not commonly employed as a clinical modality for increasing bioavailability. A few examples illustrate its efficacy. Kaila et al. studied the absorption kinetics of timolol following topical ocular administration to healthy volunteer subjects with eyelid closure, nasolacrimal occlusion (NLO), or normal blinking (43). NLO reduced total timolol systemic absorption, although, in some subjects, the initial absorption was enhanced. In another example, Zimmerman et al. showed that there were lower fluorescein anterior chamber levels and a shorter duration of fluorescein in the absence of NLO or eyelid closure (44). Systemic drug absorption in normal subjects was reduced more than 60% with these techniques. Linden and Aim studied the effect of tear drainage on intraocular penetration of topically applied fluorescein in healthy human eyes using fluorophotometry (45). Upper and lower punctal plugs in one eye caused a significant (p < 0.025) increase in aqueous humor fluorescein concentrations one to eight hours postdose of 20 |iL of 2% solution of sodium fluorescein in the lower conjunctival sac. Compressing the tear sac and/or closing the eyelids for one minute after application had no effect on corneal or aqueous levels of fluorescein. Lee et al. evaluated the effect of NLO on the extent of systemic absorption following topical ocular administration of various adrenergic drugs (46). Table 2

summarizes the results of this study (see page 135). Hydrophilic atenolol and lipophilic betaxolol, which were not absorbed into the circulation as well as timolol and levobunolol, were not affected in their systemic absorption by five minutes of NLO. However, systemic bioavailability decreased 80% by prolonging precorneal retention of the dose to 480 minutes. It was concluded that modest formulation changes will have little effect on systemic absorption for extremely hydrophilic drugs. Drugs similar in lipophilicity to timolol will be well absorbed systemically, while extremely hydrophilic drugs or extremely lipophilic drugs will be absorbed to a lesser extent. The most likely explanation that NLO is not used more widely as a clinical strategy is the uncertainty of patient compliance, and hence the additional variability in efficacy.

As alluded to earlier in this chapter, the rate and extent of systemic absorption via the conjunctiva relative to corneal absorption is dependent on the physicochemical properties of a drug or its formulation. Ahmed and Patton showed that the conjunctival pathway is particularly important for drugs with low corneal permeability and that noncorneal permeation is limited by nonproductive loss to the systemic circulation (30). Hitoshe et al. demonstrated that drugs and prodrugs could be designed to reduce conjunctival absorption selectively and thus suppress systemic exposure (47). This can be accomplished by taking advantage of the effectively lower lipophilicity of the conjunctiva versus that of the cornea. Ashton et al. studied the influence of pH, tonicity, BAC, and EDTA on conjunctival and cornea penetration of four P-blockers: atenolol, timolol, levobunolol, and betaxolol (48). Isolated pigmented rabbit conjunctiva and cornea were used. The conjunctiva was more permeable than cornea, and formulation changes had greater influence on corneal versus conjunctival penetration. This was particularly true for the hydrophilic compounds; therefore, changes in formulation can affect both ocular and systemic absorption.

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