Pharmacokinetic model for in vivo/in vitro correlation of intravitreal drug delivery

Tojo, Kakuji; Isowaki, Akiharu

doi:10.1016/s0169-409x(01)00187-9

Cited by 30 publications

(17 citation statements)

References 15 publications

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“…2), whereas a chemical like SNP is unlikely to reach the retina from the aqueous chamber. 26,27 The mechanism by which NO causes apoptosis of photoreceptors is unclear. One possibility is that it leads to an excessive build-up of cGMP in photoreceptors.…”

Section: Discussionmentioning

confidence: 99%

Metipranolol Blunts Nitric Oxide-Induced Lipid Peroxidation and Death of Retinal Photoreceptors: A Comparison with Other Anti-Glaucoma Drugs

Osborne

Wood

2004

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To determine the effect of the nitric oxide donor sodium nitroprusside (SNP) on rat retinas and to see whether detrimental changes could be attenuated by known antiglaucoma drugs. METHODS. SNP was injected into the rat eye and retinas were analyzed by the terminal-deoxynucleotidyl transferase dUTPlinked nick end labeling (TUNEL) procedure and by immunohistochemistry. In some instances, retinal homogenates were analyzed by immunoblot for proteins associated with either photoreceptors or with cell death. Analysis of lipid peroxidation in retinal homogenates was by the thiobarbituric acid reactive species (TBARS) formation method. RESULTS. SNP caused an increase in the number of retinal photoreceptors labeled for DNA breakdown by the TUNEL procedure and for caspase-3 and Bcl-2. After intravitreal injection of SNP, breakdown of poly(ADP-ribose) polymerase and an increase in the level of active forms of caspase-3 and Bcl-2 were detected. Furthermore, photoreceptor-specific rhodopsin kinase was reduced. SNP also stimulated formation of TBARS in retinal homogenates, occurring to a greater extent in retinas from young Royal College of Surgeons rats lacking photoreceptor degeneration. This supports the view that the photoreceptors are the prime target for SNP. Significantly, of several antiglaucoma drugs tested only metipranolol and its active metabolite, desacetylmetipranolol, blunted the SNP-induced retinal changes. CONCLUSIONS. Of all antiglaucoma drugs tested, only metipranolol was able to attenuate SNP-induced lipid peroxidation and activation of apoptosis in photoreceptors. Because oxidative injury has been implicated in the pathogenesis of certain ocular diseases, these findings could prove to be of clinical significance. (Invest Ophthalmol Vis Sci.

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Section: Discussionmentioning

confidence: 99%

Metipranolol Blunts Nitric Oxide-Induced Lipid Peroxidation and Death of Retinal Photoreceptors: A Comparison with Other Anti-Glaucoma Drugs

Osborne

Wood

2004

Invest. Ophthalmol. Vis. Sci.

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“…6 However, less than 5% of topically applied therapeutic agent passes through the cornea because of tear flow drainage, dilution by blinking, corneal diffusion resistance, and aqueous humor washout. 6,16,39 Systemic administration of biologically active agents often fails to deliver to some target sites at therapeutic levels because of the blood-retina barrier and the blood-aqueous barrier. 10 For effective treatment, large systemic doses are often required, which can cause systemic adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Study of Ocular Transport of Drugs Released from an Intravitreal Implant Using Magnetic Resonance Imaging

et al. 2005

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Ensuring optimum delivery of therapeutic agents in the eye requires detailed information about the transport mechanisms and elimination pathways available. This knowledge can guide the development of new drug delivery devices. In this study, we investigated the movement of a drug surrogate, Gd-DTPA (Magnevist) released from a polymer-based implant in rabbit vitreous using T1-weighted magnetic resonance imaging (MRI). Intensity values in the MRI data were converted to concentration by comparison with calibration samples. Concentration profiles approaching pseudosteady state showed gradients from the implant toward the retinal surface, suggesting that diffusion was occurring into the retinal-choroidal-scleral (RCS) membrane. Gd-DTPA concentration varied from high values near the implant to lower values distal to the implant. Such regional concentration differences throughout the vitreous may have clinical significance when attempting to treat ubiquitous eye diseases using a single positional implant. We developed a finite element mathematical model of the rabbit eye and compared the MRI experimental concentration data with simulation concentration profiles. The model utilized a diffusion coefficient of Gd-DTPA in the vitreous of 2.8 x 10(-6) cm2 s(-1) and yielded a diffusion coefficient for Gd-DTPA through the simulated composite posterior membrane (representing the retina-choroidsclera membrane) of 6.0 x 10(-8) cm2 s(-1). Since the model membrane was 0.03-cm thick, this resulted in an effective membrane permeability of 2.0 x 10(-6) cm s(-1). Convective movement of Gd-DTPA was shown to have minimal effect on the concentration profiles since the Peclet number was 0.09 for this system.

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“…8) A resulting set of ordinary differential equations are numerically solved by Gear's method. 9) To test the accuracy of the present modified cylindrical approach for analyzing the drug transport in the spherical eye, the numerical solution is compared with the analytical solution for a special case where we assume the constant diffusion coefficient throughout the spherical eye tissue. The diffusion coefficient in the space between the outside cylinder and the inside sphere is assumed to be 1000 times larger than that in the vitreous body since the diffusion resistance outside the inscribed sphere can be neglected under this condition.…”

Section: Methods Of Solutionmentioning

confidence: 99%

“…The appropriate initial and boundary conditions are described by assuming the pseudo-steady state approach (PSSA) 8,9) :…”

Section: )mentioning

confidence: 99%

A Pharmacokinetic Model for Ocular Drug Delivery

Tojo

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Pharmacokinetics of ocular drugs has frequently been analyzed by a conventional multicompartment model, 1) which assumes a homogeneous distribution of drugs in each ocular tissue. In spite of the usefulness and wide acceptance, this model may be limited in use. A major drawback of the compartment model is a lack of detailed information on the local concentration distribution in the eye. Pharmacological response is in general a function of the local tissue concentration at the site of action rather than the mean aqueous humor concentration monitored widely under in vivo conditions. Elimination routes in or on the eye also affect the local tissue concentration. Therefore the concentration in the aqueous chamber and in the vitreous body is not homogeneous but distribute complicatedly according to the elimination rate across the surrounding tissues. The animal data reported in the literature have often shown that the mean aqueous concentration, based on a simple compartment model, does not well correlate the pharmacological response because of an anti-clockwise hysteresis loop between the pharmacokinetic and pharmacodynamic relationship.2) These phenomena were widely analyzed by an effective compartment model in the literature.2) However the pharmacological response may directly be related with the local target concentration if we can evaluate the local concentration distribution.Drug movement in the eye may be better described by diffusion model based on Fick's second law of diffusion, since the events taking place in the various eye tissues depend usually upon the local concentration instead of the mean concentration throughout ocular tissues. In the present study, we have developed a diffusion model assuming a modified cylindrical eye for the pharmacokinetics of ocular drug delivery. The present model can predict the time course of the local tissue concentration in the eye following a variety of ocular drug delivery including topical instillation, systemic administration, transdermal delivery and vitreous injection and implantable delivery. In the present ocular pharmacokinetic model, it is essential to evaluate the model parameters such as the diffusion coefficient and the partition coefficient in various ocular tissues. The model parameters have been determined from in vitro experiments designed independently from in vivo experiments.3-6) The diffusion coefficient of a drug across ocular tissues may depend on the chemical structure and the physicochemical properties as well as the molecular weight of the drug. Maurice and Mishima, however, have found that the diffusion coefficient in ocular tissues is mainly influenced by the molecular weight of the drug. 1) Spherical, Modified Cylindrical, Eye ModelThe present pharmacokinetic model for ocular drug delivery assumes a spherical, modified cylindrical, eye as shown in Fig. 1. The diffusion coefficient of a drug varies not only among tissues but in each ocular tissue such as in the lens.7) The drug elimination from the eye assumes to occur across three different di...

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Pharmacokinetic model for in vivo/in vitro correlation of intravitreal drug delivery

Cited by 30 publications

References 15 publications

Metipranolol Blunts Nitric Oxide-Induced Lipid Peroxidation and Death of Retinal Photoreceptors: A Comparison with Other Anti-Glaucoma Drugs

Metipranolol Blunts Nitric Oxide-Induced Lipid Peroxidation and Death of Retinal Photoreceptors: A Comparison with Other Anti-Glaucoma Drugs

Study of Ocular Transport of Drugs Released from an Intravitreal Implant Using Magnetic Resonance Imaging

A Pharmacokinetic Model for Ocular Drug Delivery

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