Albumin Levels in Tear Film Modulate the Bioavailability of Medically-Relevant Topical Drugs

Abstract

The breakdown of blood-tear barrier that occurs with ocular pathology allows for large amounts of albumin to leak into the tear fluid. This process likely represents an important restriction to drug absorption in ophthalmology, as only the unbound drug is transported across the ocular tissue barriers to exert its pharmacologic effect. We aimed to investigate the effects of albumin levels in tears on the bioavailability of two commonly used ophthalmic drugs: tropicamide, an antimuscarinic that produces mydriasis and cycloplegia, and latanoprost, a PGF2a analog used for the treatment of glaucoma. Eight female beagle dogs underwent a randomized, vehicle-controlled crossover trial. For each dog, one eye received 30 µl of artificial tears (control) or canine albumin (0.4 or 1.5%) at random, immediately followed by 30 µl of 1% tropicamide (2 days, 24 h washout) or 0.005% latanoprost (2 days, 72 h washout) in both eyes. Pupil diameter (digital caliper) and intraocular pressure (IOP; rebound tonometry) were recorded at various times following drug administration (0 to 480 min) and compared between both groups with a mixed model for repeated measures. Albumin in tears had a significant impact on pupillary diameter for both tropicamide (P ≤ 0.001) and latanoprost (P ≤ 0.047), with no differences noted between 0.4% and 1.5% concentrations. Reduction in the maximal effect (pupil size) and overall drug exposure (area under the effect time-curve of pupil size over time) were significant for tropicamide (6.2-8.5% on average, P ≤ 0.006) but not for latanoprost (P ≥ 0.663). The IOP, only measured in eyes receiving latanoprost, was not significantly impacted by the addition of either 0.4% (P = 0.242) or 1.5% albumin (P = 0.879). Albumin in tear film, previously shown to leak from the conjunctival vasculature in diseased eyes, may bind to topically administered drugs and reduces their intraocular penetration and bioavailability. Further investigations in clinical patients and other commonly used ophthalmic medications are warranted.

An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface

“…249 although this method should account for differences between subjects such as greater tear volumes in dogs of larger body weight. 123 Another aspect to consider in the study design is the assessment of drug kinetics in diseased eyes, rendering the study results more clinically applicable (see Section 4.2); in fact, tear film concentrations and ocular bioavailability are likely to differ in healthy versus diseased eyes (e.g., excessive lacrimation, increased absorption into congested conjunctival vessels, albumin binding), 215,278 yet the majority of ocular studies to date are conducted in healthy individuals which is a clear limitation for translation of research findings from bench to bedside.…”

“…164 Of note, the impact of lacrimal albumin on the pharmacological activity of a given drug is likely modulated by various factors including the concentration of the formulation, the mechanism of action and the potency of the drug for its biological target. 278 • Reduced bioavailability for ocular surface targets: Drug-albumin interactions in the tear film could also be detrimental for management of ocular surface disorders, for instance reducing the efficacy of therapeutics for bacterial keratitis as only the unbound portion of an antibiotic is microbiologically active. 172 Preliminary experiments conducted by the authors showed that the presence of albumin results in higher minimal inhibitory concentrations (i.e., reduced susceptibility) for various antibiotics against common bacterial isolates in dogs.…”

“…For topical drug administration, the authors recommend using an experimental model of blood-tear barrier breakdown (e.g., histamine-induced conjunctivitis or alkali burn models) 200,313 so that albumin and other relevant proteins are already present on the ocular surface at the time the drug mixes with the tear film. 278 For systemic drug administration, the authors suggest conducting a preliminary experiment to assess whether conjunctival inflammation affects tear film concentrations to a significant extent. If not, pharmacological assessment in healthy eyes should be sufficient.…”

“…An alternative is to use a larger sample size and randomly allocate each time point to a subset of individuals or eyes (e.g., 40 eyes with n = 5 eyes for eight separate time points), 211 although this method should account for differences between subjects such as greater tear volumes in dogs of larger body weight 123 4.2); in fact, tear film concentrations and ocular bioavailability are likely to differ in healthy versus diseased eyes (e.g., excessive lacrimation, increased absorption into congested conjunctival vessels, albumin binding), 215,278 yet the majority of ocular studies to date are conducted in healthy individuals which is a clear limitation for translation of research findings from bench to bedside. Tear collection with Schirmer strips : It is important to homogenize the volume collected within and between subjects by standardizing the extent of strip wetness (≥20 mm mark)—this approach limits the variability in tear concentrations related to the collection method itself 214,215 . The amount of wetness is then converted to a volume (µl) to calculate actual tear film concentrations 270 ; data reporting is otherwise limited to µg/g of strip 211,244 .…”

Impact of diurnal variation, sex, tear collection method, and disease state on tear protein levels in dogs

“…While serum albumin in tears might participate in corneal wound healing or provide antioxidative and anti-inflammatory activities, 29,30 excess levels of albumin could result in detrimental effects to the eye. Indeed, high albumin concentrations in tears were shown to decrease the bioavailability of topically administered drugs, 17,31,32 as only the unbound fraction of a drug can penetrate through the corneal barrier. Further, albumin could theoretically reduce the efficacy of topical antibiotics applied to the eye, as shown for skin wounds, 33 as only the unbound fraction of an antibiotic is microbiologically active.…”