Mechanistic Studies on Transcorneal Permeation of Fluorometholone

Sieg, James W.; Robinson, Joseph R.

doi:10.1002/jps.2600700915

Cited by 25 publications

(10 citation statements)

References 9 publications

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“…The epithelial concentration reached a peak within 5 min, whereas in the stroma-endo thelium the peak level of prednisolone was achieved at 60 min. Prednisolone rapidly penetrates the intact corneal epithelium and accumulates in hy drophilic stromal layers of the cornea, a be havior being highly similar to fluorometholone [12], but distinct from pilocarpine. Ow ing to the lipid-soluble nature of both fluorometholone and prednisolone [13], the epi- thelium does not act as a barrier to these ste roids, in contrast to lipid-insoluble pilocar pine.…”

Section: Corneal Epithelium and Stromaendothelium Concentration-time mentioning

confidence: 99%

Intraocular Penetration Kinetics of Prednisolone after Subconjunctival Injection in Rabbits

Tsuji¹,

Tamai²,

Sasaki³

1988

Ophthalmic Res

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Prednisolone concentrations in cornea, aqueous humor, and vitreous humor and the residual amount in conjunctival tissue were assayed by high-performance liquid chromatography during a 14-hour period after subconjunctival injection of prednisolone sodium succinate in rabbits. Prednisolone was concentrated in the corneal epithelium and reached a peak within 5 min, whereas the peak level of prednisolone in stroma-endothelium was achieved 1 h after the injection. There was an apparent linear binding of prednisolone with the ocular tissue homogenates and fluids except for the vitreous humor. However, the protein binding of prednisolone with vitreous humor showed marked concentration dependency. A pharmacokinetic model involving a rapid conversion to prednisolone from its ester prodrug, first-order transfer to various tissues, and first-order elimination of unbound prednisolone from vitreous humor succeeded in predicting the observed concentration-time profiles of prednisolone in various ocular tissues and fluids after subconjunctival injection at three different doses: 0.1, 1.0, and 10.0 mg/kg. The present model predicted that absorption into precorneal area and epithelium and direct penetration into aqueous humor and vitreous humor are 1.7, 0.1, and 0.2% of the applied dose, respectively, and that almost the entire dose (98%) is absorbed into the systemic circulation, with a half-life of 38 min.

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Section: Corneal Epithelium and Stromaendothelium Concentration-time mentioning

confidence: 99%

Intraocular Penetration Kinetics of Prednisolone after Subconjunctival Injection in Rabbits

Tsuji¹,

Tamai²,

Sasaki³

1988

Ophthalmic Res

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“…The initial model was developed against cornea and AH concentration time course data following the administration of 50 μL of a 4E-5 M Flm solution to rabbit ( 33 ). Figure 1 (dashed lines) presents the simulation results for the model with all in silico-estimated OCAT™ parameters except for both cornea epithelium and stroma permeabilities that were based on in vitro measurements ( 32 ).…”

Section: Resultsmentioning

confidence: 99%

“…The initial model was developed against cornea and AH concentration time course data following the administration of a saturated solution of Flm (50 μL of Flm solution 4.0E-5 M) to rabbit ( 33 ). In vitro cornea permeability (1.66E-5 cm/s) ( 32 ) was first tested to describe the observed data.…”

Section: Methodsmentioning

confidence: 99%

Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations

et al. 2020

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Purpose The purpose of this study is to show how the Ocular Compartmental Absorption & Transit (OCAT™) model in GastroPlus® can be used to characterize ocular drug pharmacokinetic performance in rabbits for ointment formulations. Methods A newly OCAT™ model developed for fluorometholone, as well as a previously verified model for dexamethasone, were used to characterize the aqueous humor (AH) concentration following the administration of multiple ointment formulations to rabbit. The model uses the following parameters: application surface area (SA), a fitted application time, and the fitted Higuchi release constant to characterize the rate of passage of the active pharmaceutical ingredient from the ointment formulations into the tears in vivo. Results Parameter sensitivity analysis was performed to understand the impact of ointment formulation changes on ocular exposure. While application time was found to have a significant impact on the time of maximal concentration in AH, both the application SA and the Higuchi release constant significantly influenced both the maximum concentration and the ocular exposure. Conclusions This initial model for ointment ophthalmic formulations is a first step to better understand the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug pharmacokinetic performance in rabbits.

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“…These effects were observed even in the case of a thorough washout of the preparation. It has been suggested that some drugs are absorbed by iridial pigment cells which then gradually released them into the aqueous humor [11,12,13,14]. Thus, one possible explanation is: if iridial pigment cells absorbed pilocarpine and the absorbed pilocarpine were gradually released, then the washout ofpilocarpine would be ineffective for a long period.…”

Section: Discussionmentioning

confidence: 99%

Desensitization of the isolated bovine iris sphincter muscles by pilocarpine

1988

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We investigated the effect of pilocarpine on the bovine iris sphincter. This muscle contracted in a dose-dependent manner from 2 x 10(-6) M, with a maximal response at 3 x 10(-3) M. The ED50 values was (1.6 +/- 0.3) x 10(-4) M. Pilocarpine generated a desensitization while desensitization was not significant in the case of other cholinergic agents such as acetylcholine (Ach) and carbachol. Desensitization was profoundly increased in the presence of Ach, neostigmine or eserine: the responses to the second and third trials of pilocarpine were reduced to approximately 8-10% or 30% of the corresponding first responses. Pilocarpine reportedly releases transmitters and alters choline-acetyltransferase activity. These results taken together suggest that either variable Ach synthesis, inhibitory transmitter release or possible toxic action in high concentrations may be involved in the pilocarpine-induced responses of the bovine iris sphincter muscle. The desensitization and partial agonist-antagonist action of pilocarpine could not explain the characteristics of the bovine iris sphincter muscle.

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Mechanistic Studies on Transcorneal Permeation of Fluorometholone

Cited by 25 publications

References 9 publications

Intraocular Penetration Kinetics of Prednisolone after Subconjunctival Injection in Rabbits

Intraocular Penetration Kinetics of Prednisolone after Subconjunctival Injection in Rabbits

Ocular Physiologically Based Pharmacokinetic Modeling for Ointment Formulations

Desensitization of the isolated bovine iris sphincter muscles by pilocarpine

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