Peak Aqueous Humor Research Articles

Enhancing Ocular Bioavailability of Ciprofloxacin Using Colloidal Lipid-Based Carrier for the Management of Post-Surgical Infection.

Conjunctivitis and endogenous bacterial endophthalmitis mostly occurred after ophthalmic surgery. Therefore, the present study aimed to maximize the ocular delivery of ciprofloxacin (CPX) using colloidal lipid-based carrier to control the post-surgical infection. In this study, CPX was formulated as ophthalmic liposomal drops. Two different phospholipids in different ratios were utilized, including phosphatidylcholine (PC) and dimyrestoyl phosphatidylcholine (DMPC). The physiochemical properties of the prepared ophthalmic liposomes were evaluated in terms of particle size, entrapment efficiency, polydispersity index, zeta potential, and cumulative CPX in-vitro release. In addition, the effect of sonication time on particle size and entrapment efficiency of CPX ophthalmic drops was also evaluated. The results revealed that most of the prepared formulations showed particle size in nanometer size range (460–1047 nm) and entrapment efficiency ranging from 36.4–44.7%. The antibacterial activity and minimum inhibitory concentration (MIC) were investigated. Ex vivo antimicrobial effect of promising formulations was carried out against the most common causes of endophthalmitis microorganisms. The pharmacokinetics of the prepared ophthalmic drops were tested in rabbit aqueous humor and compared with commercial CPX ophthalmic drops (Ciloxan®). Observed bacterial suppression was detected in rabbit’s eyes conjunctivitis with an optimized formulation A3 compared with the commercial ophthalmic drops. CPX concentration in the aqueous humor was above MIC against tested bacterial strains. The in vivo data revealed that the tested CPX drops showed superiority over the commercial ones with respect to peak aqueous humor concentration, time to reach peak aqueous humor concentration, elimination rate constant, half-life, and relative bioavailability. Based on these results, it was concluded that the prepared ophthalmic formulations significantly enhanced CPX bioavailability compared with the commercial one.

Ocular penetration of topically applied 1% tigecycline in a rabbit model.

To evaluate ocular penetration of topically applied 1% tigecycline. Forty-two New Zealand White rabbits were divided into 3 groups. A 50 µL drop of 1% tigecycline was administered in group 1. In groups 2 and 3, the drop was administered every 15min for 60min (keratitis protocol). Aqueous humor samples in groups 1 and 2 were collected under general anesthesia at 15, 30, 45, 60, 120, and 180min after the last drop. All animals in group 3 were euthanatized. Cornea, vitreous and blood samples were collected 60 and 120min after the last drop. Tigecycline concentrations were measured using high performance liquid chromatography-mass spectrometry (LC-MS/MS). The peak aqueous humor tigecycline concentration [mean 0.73±0.14 mg/L (SD) and 2.41±0.14 mg/L, respectively] occurred 45min after topical drug application in groups 1 and 2. Group 3 mean values in the cornea, and vitreous, were 3.27±0.50 µg/g, and 0.17±0.10 mg/L at 60min and 3.17±0.77 µg/g and 0.20±0.07 mg/L at 120min, respectively. Tigecycline serum concentrations were negligible. Tigecycline levels in the aqueous humor in groups 1 and 2, and in the cornea in group 3 exceeded the minimum inhibitory concentrations of most gram-positive organisms that cause bacterial keratitis and endophthalmitis.

Pharmacokinetics of Azithromycin and Moxifloxacin in Human Conjunctiva and Aqueous Humor During and After the Approved Dosing Regimens

To evaluate the ocular pharmacokinetics of azithromycin and moxifloxacin in human conjunctiva and aqueous humor in subjects undergoing cataract surgery. Multicenter, open-label, randomized study. Subjects scheduled for routine cataract surgery and with normal-appearing conjunctiva were eligible. One conjunctival biopsy sample and 1 aqueous humor sample were obtained from subjects randomly assigned to 1 of 10 prespecified time points (1 to 312 hours) after treatment initiation of azithromycin ophthalmic solution 1% or moxifloxacin ophthalmic solution 0.5%. Samples were assayed using liquid chromatography tandem mass spectrometry. Azithromycin 1% provided high concentrations (peak level, 559.7 μg/g) in human conjunctiva that were sustained at levels 1 to 2 orders of magnitude higher than those of moxifloxacin 0.5% throughout the 7-day dosing period and for at least 7 days thereafter. Azithromycin also showed an extended half-life (65.7 hours) in conjunctiva relative to that of moxifloxacin (28.6 hours). Accordingly, the concentration of azithromycin was maintained well above the minimum inhibitory concentration required for inhibition of growth of 90% of tested bacterial isolates for at least 7 days, whereas moxifloxacin conjunctival levels fell to levels at or less than the minimum inhibitory concentration required for inhibition of growth of 90% of tested bacterial isolates approximately 24 hours after the last dose. Peak aqueous humor concentration of moxifloxacin was higher (0.77 μg/mL) than that of azithromycin (0.053 μg/mL). No clinically relevant safety findings were observed. Azithromycin 1% demonstrated high, therapeutic levels in the conjunctiva that were maintained up to 7 days after completion of a 1-week dosing regimen. Aqueous humor levels, however, were subtherapeutic with this dosing regimen. In comparison, moxifloxacin achieved lower conjunctival tissue levels, but higher aqueous humor levels.

In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac

To evaluate the aqueous humor concentrations and cyclooxygenase (COX) inhibitory activities of nepafenac, amfenac, ketorolac, and bromfenac after topical ocular administration of Nevanac (nepafenac 0.1%), Acular LS (ketorolac 0.4%), or Xibrom (bromfenac 0.09%). Five private ophthalmology practices throughout the United States. Patients requiring cataract extraction were randomized to 1 of 3 treatment groups: Nevanac, Acular LS, or Xibrom. Patients were administered 1 drop of the test drug 30, 60, 120, 180, or 240 minutes before cataract surgery. At the time of paracentesis, an aqueous humor sample was collected and later analyzed for drug concentration. In addition, COX-1 (homeostatic) and COX-2 (inducible) inhibitory activities of nepafenac, amfenac, ketorolac, and bromfenac were determined via the in vitro measurement of prostaglandin E(2) (PGE(2)) inhibition. Seventy-five patients participated in the study. The prodrug nepafenac had the shortest time to peak concentration and the greatest peak aqueous humor concentration (C(max)). The C(max) of nepafenac was significantly higher than that of the other drugs (P<.05), including the higher-concentration ketorolac (0.4%). The area under the curve (AUC) of nepafenac was significantly higher (P<.05) than the AUCs of amfenac, ketorolac, and bromfenac. The combined AUCs of nepafenac and amfenac were the highest of all drugs tested (P<.05). Ketorolac showed the most potent COX-1 inhibition, whereas amfenac was the most potent COX-2 inhibitor. The PGE(2) aqueous humor levels of each study medication were highly variable; as a result, meaningful interpretation of the data was not possible. Nepafenac showed significantly greater ocular bioavailability and amfenac demonstrated greater potency at COX-2 inhibition than ketorolac or bromfenac.

Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection

Purpose To describe the pharmacokinetics occurring after the direct injection of triamcinolone acetonide into the vitreous humor of humans. Design Interventional case series. Participants Five patients who received a single 4-mg intravitreal injection of triamcinolone acetonide. Methods An aqueous humor sample was obtained from 5 eyes via an anterior chamber paracentesis at days 1, 3, 10, 17, and 31 after injection. At each visit, visual acuity and intraocular pressure were measured and indirect ophthalmoscopy was performed. A fluorescein angiogram was carried out at day 10. Concentrations were determined using high performance liquid chromatography; pharmacokinetic analysis was carried out using PK Analyst, an iterative, nonlinear, weighted, least-squares regression program. Main outcome measures Intraocular concentrations of triamcinolone were measured and population pharmacokinetic parameters were calculated. Results Pharmacokinetic data followed a two-compartment model. Peak aqueous humor concentrations ranged from 2151 to 7202 ng/ml, half-lives from 76 to 635 hours, and the integral of the area under the concentration-time curve (AUC 0-t) from 231 to 1911 ng/h per milliliter. After a single intravitreal injection of triamcinolone, the mean elimination half-life was 18.6 days in nonvitrectomized patients. The half-life in a patient who had undergone a vitrectomy was shorter at 3.2 days. Conclusions There was considerable intrasubject variation among peak concentration, AUC 0-t values, and elimination half-lives. After intravitreal injection, measurable concentrations of triamcinolone would be expected to last for approximately 3 months (93 ± 28 days) in the absence of a vitrectomy. Because triamcinolone pharmacokinetics were characterized only in elderly patients with macular edema, the results cannot be extrapolated to other patient populations.

Ocular Penetration of Cefepime Following Systemic Administration in Humans

To investigate the penetration of cefepime (a fourth generation cephalosporin) into the aqueous humor after single-dose intravenous administration in humans. Before receiving cataract surgery, 30 patients received randomly 1 g (group 1, 15 patients) and 2 g (group 2, 15 patients) single intravenous injection of cefepime before surgery. Samples of aqueous humor and serum were obtained at 0.5, 1, 2, 4, and 12 hours after injection. Three patients were sampled each time for 1 g and 2 g of cefepime. Samples were assayed for cefepime concentrations with high performance liquid chromatography (HPLC). All the patients had detectable cefepime in their aqueous humor and serum measurable by HPLC. A mean peak aqueous humor level was 5.16 +/- 0.88 microg/mL in group 1 and 5.87 +/- 1.64 microg/mL in group 2 at 0.5 hour after injection. The mean level of cefepime in aqueous humor decreased after 0.5-hour measurements in both groups and was measured as 0.82 +/- 0.21 microg/mL in group 1 and 2.04 +/- 0.30 microg/mL in group 2 at 12 hours after injection. Aqueous humor levels of cefepime after single IV injection were above the minimum inhibitory concentration (MIC90) for most ocular pathogens, but the duration of exposure to an antibiotic was not sufficient for therapeutic effect.

Retinal safety of oral and topical ofloxacin in rabbits.

Ofloxacin is a broad spectrum fluoroquinolone antibiotic with good ocular penetration. We investigated the potential for retinal toxicity associated with increased intraocular penetration following intensive topical, oral, and combined topical and oral administration. We confirmed ofloxacin concentrations in aqueous and vitreous following these forms of administration. Rabbits received either topical, oral, or a combination of oral and topical ofloxacin. Topical administration consisted of one drop of ofloxacin 0.3% drops given every thirty minutes for a total of eight doses. Oral ofloxacin was administered at a dose of 10 mg (4 mg/kg for average weight 2.5 kg rabbit) every 12 hours for a total of three doses. Six rabbits were followed longitudinally for 4 weeks for evidence of retinal toxicity by indirect ophthalmoscopy and serial ERGs. Electron and light microscopic histopathologic examination of the retina were performed 4 weeks following drug administration. To verify intraocular penetration, ten rabbits received identical dosing schedules followed by HPLC measurement of aqueous and vitreous drug concentrations at 1, 4, 8, 12, and 24 hours following dose completion. No evidence of retinal toxicity was detected by indirect ophthalmoscopy, electroretinography, or histopathological examination. Vitreous ofloxacin levels were highest after combined oral and topical administration, peaking at 0.892 microgram/ml 8 hours following dosage completion. The peak vitreous level following oral administration was 0.230 microgram/ml and 0.026 microgram/ml following topical administration. Peak aqueous humor levels were achieved one hour following drug administration and were 11.400 micrograms/ml after topical, 0.206 microgram/ml after oral, and 8.180 micrograms/ml after combined administration. Our study suggests that intensive topical and oral ofloxacin administration does not cause retinal toxicity in rabbits, despite achieving effective aqueous and vitreous humor antimicrobial concentrations.

Toxicity and Pharmacokinetics of Ciprofloxacin

Ciprofloxacin is a fluorinated quinolone antibiotic with a broad spectrum of activity against both gram positive and gram negative organisms. Previous studies have indicated that oral or parenteral preparations of ciprofloxacin resulted in therapeutic concentrations in the aqueous humor but intravitreal levels were found to be only marginally higher than the MIC90 for gram positive cocci. Toxicity was evaluated following intravitreal doses of ciprofloxacin injected into the mid-vitreous cavity of one eye of pigmented rabbits. As a control, an identical volume of normal saline was injected into the fellow eye. Four doses of ciprofloxacin were studied, 100 micrograms, 250 micrograms, 500 micrograms and 1000 micrograms. Electroretinograms (ERGs) were recorded prior to injection and 1, 7 and 14 days after injection. These were analyzed as b-wave amplitude ratios between treated and untreated eyes. On ophthalmoscopic examination focal areas of retinitis were observed following injection of both 500 micrograms and 1000 micrograms of ciprofloxacin but not at 250 micrograms. Additionally, ERG amplitude ratios were significantly reduced following the 1000 micrograms dose. At the 100 or 250 micrograms ciprofloxacin dose histological sections are comparable with control eyes and appear normal; ERG ratios were unchanged from the baseline level and careful indirect ophthalmoscopic examination revealed no alterations. Pharmacokinetic analysis after single intravitreal injection of 250 micrograms of ciprofloxacin (N = 3 rabbits/dose) disclosed vitreous fluid levels (microgram/ml) of 146 at 0 hr, 77 at 4 hr, 32 at 8 hr, 0.49 at 24 hr and 0.24 at 48 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Ophthalmic Beta-Blockers: Determination of Plasma and Aqueous Humor Levels by a Radioreceptor Assay Following Multiple Doses

We determined the binding affinities of multiple doses of four ophthalmic beta-blockers, timolol, betaxolol, levobunolol and carteolol, to the beta-1 and beta-2 receptors. With a Ki value of 0.39 nM and 0.36 nM for the beta-1 and beta-2 receptors, respectively, levobunolol shows the highest binding affinity to both beta receptors. The Ki values of timolol (1.97 nM for the beta-1 receptor and 2.0 nM for the beta-2 receptor) and of carteolol (0.83 nM and 0.85 nM for the beta-1 and beta-2 receptors, respectively) are characteristic of a nonspecific beta-blocker. On the contrary, betaxolol is a beta-1 specific antagonist (Ki of 23.33 nM) and has a very low binding affinity to the beta-2 receptor (Ki of 200.00 nM). With a radioreceptor assay, levels of beta-antagonist were measured in the plasma and aqueous humor 1 hour and 12 hours after instillation of 50 microliters of 0.5% or 2% each of the four beta-blockers into the rabbit eye. At 1 hour after administration, the plasma levels of timolol, levobunolol, and carteolol are 9.89 ng/ml, 1.60 ng/ml and 8.00 ng/ml, respectively; such levels of 11.82 to 29.22 times the respective Ki values cause a virtually total blockade of both beta-1 and beta-2 receptors and suggest significant systemic absorption. Betaxolol has a peak 1 hour plasma level of 22.28 ng/ml, which is equivalent to only 3.08 times its Ki for the beta-1 receptor and 0.36 times its Ki for the beta-2 receptor; it has less systemic beta-1 blocking activity than the other three drugs and very minimal systemic beta-2 blocking activity. Peak aqueous humor concentrations of all 4 beta-blockers are extremely elevated at 1 hour after administration (timolol 1613.58 ng/ml; betaxolol 866.06 ng/ml; levobunolol 750.89 ng/ml; and carteolol 859.18 ng/ml). Such levels of 14 to 7192 times the respective Ki values should cause a virtually complete blockade of both beta-1 and beta-2 receptors in the iris-ciliary body complex. At 12 hours after administration, plasma levels of all four beta blockers remain moderately elevated (timolol 0.94 ng/ml; betaxolol 9.43 ng/ml; levobunolol 0.66 ng/ml; and carteolol 1.61 ng/ml). Trough aqueous humor levels of levobunolol (43.38 ng/ml) and carteolol (92.81 ng/ml) remain elevated at least 300 times their Ki value. On the contrary, 12-hour trough aqueous humor levels of timolol (33.67 ng/ml) and betaxolol (94.86 ng/ml) have decreased to 2 to 40 times their Ki value, which may explain their requirement for twice daily administration clinically.

Toxicity and pharmacokinetics of cefepime (BMY-28142) following intravitreal injection in pigmented rabbit eyes.

We delineated the dose- and time-dependent retinal toxicity of cefepime (BMY-28142), a new third generation cephalosporin, using electroretinography in pigmented rabbit eyes. Toxicity was evaluated following intravitreal doses ranging from 0.5 to 20mg/0.1ml (N = 18). Electroretinographic patterns at one and two weeks indicated a toxic response to 20 mg of cefepime. B-waves were normal at one and two weeks for rabbits receiving doses of 0.5 to 10mg. Pharmacokinetic analysis after single intravitreal injection of 1 mg of cefepime (N = 3 rabbits/dose) disclosed the following vitreous fluid levels (ug/ml): 645 at Oh, 431 at 8h, 235 at 24h and 23 at 72h. Peak aqueous humor levels (56 ug/ml) were observed at 8h after injection. At 72h, ug/ml was detected in the aqueous fluid.

Penetration of Imipenem Into Human Aqueous and Vitreous Humor

Twenty-five patients about to undergo cataract surgery and ten patients about to undergo vitrectomy received a 1-g intravenous dose of imipenem before surgery. Specimens of aqueous or vitreous humor were then obtained and assayed for antibiotic content with a microbiologic disk agar technique. A mean peak aqueous humor level of 2.99 micrograms/ml was found at approximately two hours after administration, and a mean vitreous level of 2.53 micrograms/ml was found from two hours to three hours 15 minutes after administration. These concentrations were well above the minimum inhibitory concentration of imipenem for 90% (MIC90) of Staphylococcus epidermidis, S. aureus, and the Enterobacteriaceae commonly involved in bacterial endophthalmitis.

Systemic aminocaproic acid reduces fibrinolysis in aqueous humor.

Systemically administered aminocaproic acid has been demonstrated to reduce the incidence of secondary hemorrhage in traumatic hyphema. To directly determine the concentration of aminocaproic acid in the aqueous humor, four groups of rabbits were studied following administration of four different regimens of intravenously administered aminocaproic acid. Plasma and aqueous humor samples were assayed for drug content and antifibrinolytic activity. Peak aqueous humor concentrations of aminocaproic acid ranged from 2.5 to 33 mg/dL and varied according to the systemic dose administered. The antifibrinolytic activity paralleled the aminocaproic acid content, with a peak range from 310 to 683 s. These findings indicate a direct relationship between antifibrinolytic activity and the concentration of aminocaproic acid in aqueous humor.

Intravitreal ceftazidime in a rabbit model: dose- and time-dependent toxicity and pharmacokinetic analysis.

We delineated the dose-and time-dependent retinal toxicity of intravitreal ceftazidime using electroretinography (ERG) in phakic rabbit eyes. Toxicity was evaluated following intravitreal doses ranging from 0.5 to 50 mg/0.1 ml. Eyes were examined prior to injection, at one day, and at seven days after injection. ERG patterns at one and seven days indicated a toxic response to doses of 20 to 50 mg. Doses of 10 mg or less gave a transient depression of the B-wave at one day, but a return to normal was observed at the seven-day evaluation. Pharmacokinetic analysis following intravitreal injection of 2 mg of ceftazidime into uninfected phakic rabbit eyes disclosed vitreous levels of: 1711 micrograms/ml at 0 hr; 1340 micrograms/ml at 8 hr; 451 micrograms/ml at 24 hr; 270 micrograms/ml at 48 hr and 67 micrograms/ml at 72 hr. Peak aqueous humor level was 139 micrograms/ml 8 hr post-injection. Potentially therapeutic drug levels were obtained in the aqueous and vitreous humors following a nontoxic intravitreal dose of ceftazidime in a rabbit model.

Ceftazidime concentrations in human aqueous humor.

Two grams of ceftazidime was given to 25 patients before cataract surgery. Mean aqueous humor concentrations of 2.8, 3.2, 3.39, and 1.94 micrograms/mL were observed 30 minutes and 1, 2, 4, and 6 hours, respectively, after administration of the drug. These concentrations are many times higher than the minimum inhibitory concentration (MIC) of ceftazidime against 90% ( MIC90 ) of isolates of Escherichia coli, Klebsiella sp, Proteus mirabilis, and indole-positive Proteus sp. The peak aqueous humor level was also equivalent to or slightly higher than the MIC90 for Pseudomonas aeruginosa.

Cefoperazone Concentrations in Human Aqueous Humor after Intravenous Administration

Twenty-four patients about to undergo elective cataract surgery received either a 2-g (ten patients) or a 4-g (14 patients) intravenous infusion of cefoperazone one to six hours before surgery. The 4-g dose produced a mean peak aqueous humor concentration of 2.93 micrograms/ml at one hour; the mean concentration remained higher than 2 micrograms/ml for at least four hours. These levels, however, were never more than 90% of the minimum inhibitory concentration of cefoperazone for common bacterial ocular pathogens.

Cephradine levels in human aqueous humor.

In an attempt to investigate penetration of cephradine into the primary aqueous humor in man, we administered 500-mg and 1-g doses of cephradine orally to 27 patients about to undergo elective cataract extraction. A mean peak aqueous humor level of 0.87 microgram/mL was obtained at about three hours after the 500-mg dose. The mean peak aqueous humor level after the 1-g dose also occurred at three hours and was 1.99 microgram/mL, with a range from 0.91 to 3.25 microgram/mL. This concentration was greater than the median minimum inhibitory concentration (MIC) of cephradine for Streptococcus pneumoniae, Str pyogenes, and Staphylococcus aureus (when tested in nutrient agar) but was greater than the MIC for 90% of isolates only with Str pyogenes.

Penetration of five beta-adrenergic antagonists into the rabbit eye after ocular instillation.

Aqueous humor and serum levels of five beta-adrenergic blockers were measured using gas chromatographic techniques following ocular instillation of 1% solutions to rabbits. Octanol/buffer partition ratios were also determined. No apparent relationship was found between the peak levels of the agents in aqueous humor and their octanol/buffer partition ratios. However, peak aqueous humor levels of timolol (461 ng/100 mg) and practolol (919 ng/100 mg), whose partition ratios were less than unity, occurred somewhat later (1 h) than the peaks of propranolol (859 ng/100 mg at 30 min), oxprenolol (1,771 ng/100 mg at 30 min) or alprenolol (1,004 ng/100 mg at 10 min) whose partition ratios exceeded unity. Peak levels in serum of timolol (8.0 ng/100 microliter), propranolol (4.2 ng/100 microliter), oxprenolol (11.5 ng/100 microliter), and alprenolol (4.5 ng/100 microliter) were achieved within 10 min and reduced to less than 15% within 4 h. Peak serum levels of practolol (9.9 ng/100 microliter) occurred somewhat later (2 h) and remained high (41%) 6 h later.

Concentrations of 2-hydroxyiminomethyl- N-methylpyridinium ion in plasma and aqueous humor as indices of the toxicity of pralidoxime mesylate (P2S) for the rabbit

Plasma pralidoxime mesylate (P2S) concentrations were measured at various times up to 2 hr in female rabbits after a single injection of the im LD50 (258 mg/kg) or iv LD50 (118 mg/kg). The results indicate that plasma P2S concentrations at death are generally greater than 200 μg/ml; plasma concentrations of 90–160 μg/ml, if maintained for a few minutes, are not lethal, but if sustained, then an abrupt rise in concentration may occur with death ensuing at concentrations greater than 200 μg/ml; sustained plasma concentrations of 90 μg/ml or less are not lethal. P2S was present in measurable amounts in the aqueous humor, but always at concentrations lower than in plasma. In a separate study to define the relationship between plasma and aqueous humor P2S concentrations, rabbits were sacrificed after receiving 50% the im LD50 (129 mg/kg). At 5 min, P2S was detected in aqueous humor in concentrations 5–15% that in plasma. Peak aqueous humor concentrations were measured at 1 hr, at which time the plasma concentrations had decreased to similar values. Thereafter, plasma and aqueous humor concentrations declined at similar rates. Rabbits having im P2S injections of 40 mg/kg showed increases in intraocular tension, significant at 1 hr after injection and persisting for a further 4 hr.

Vehicle Effects on Ocular Drug Bioavailability I: Evaluation of Fluorometholone

The influences of drug concentration and vehicle composition on the corneal penetration of the steroid fluorometholone were studied in the albino rabbit. Aqueous dosing systems included a saturated solution and 0.1, 0.05, and 0.01% suspensions of micronized fluorometholone. Two different doses of a 0.1% oleaginous ointment were also studied. The results from the 0.1 and 0.05% suspensions show a peak aqueous humor steroid concentration at 30 min and a substantial sustaining effect with these two concentrations. The results also support the belief that moderate dilution of a suspension of a slowly soluble drug may not substantially lower the aqueous humor drug levels or, conversely, that use of a higher concentration suspension may not improve the aqueous humor drug concentration‐time profile. The 0.01% suspension and the saturated solution did not produce a sustaining effect. The results demonstrate for the first time that the particles present in a dose of suspension are retained within the cul‐de‐sac of the eye and contribute significantly to the amount of steroid penetrating the cornea. This finding was confirmed by a study in which the eye was rinsed with saline solution 30 min after instillation of a dose of a 0.05% suspension. The rinsing procedure prematurely terminated the sustaining effect of the suspension. The results of the ointment studies show that partitioning of the lipophilic steroid from the oleaginous vehicle has a greater rate‐limiting influence on corneal penetration than the dissolution rate parameter associated with the aqueous suspensions. Peak aqueous humor concentration was not achieved until 3 hr after dosing and was comparable to the 0.1 and 0.05% suspensions. Predosing of the eye with a saturated solution or the 0.1% suspension prior to dosing with ointment overcomes the inability of the ointment to provide adequate drug at short times following dosing. In this case, peak levels were achieved within 60 min and then maintained. The duration of aqueous humor levels and the amount penetrating from the ointment were greater than the suspensions, and these effects are discussed relative to the mechanism. Differences in aqueous humor levels produced by 25° and 50‐mg doses of ointment were minimal. A discussion of the results from all studies is presented in the context of present theories regarding the role of the lipophilic epithelial layer of the cornea as a barrier to drug penetration.