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Prediction of Passive Drug Permeability Across the Blood-Retinal Barrier

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ABSTRACT

Purpose

The purpose of this study is to develop a computational model of the physical barrier function of the outer blood-retinal barrier (BRB), which is vital for normal retinal function. To our best knowledge no comprehensive models of BRB has been reported.

Methods

The model construction is based on the three-layered structure of the BRB: retinal pigment epithelium (RPE), Bruch’s membrane and choriocapillaris endothelium. Their permeabilities were calculated based on the physical theories and experimental material and permeability studies in the literature, which were used to describe diffusional hindrance in specific environments.

Results

Our compartmental BRB model predicts permeabilities with magnitudes similar to the experimental values in the literature. However, due to the small number and varying experimental conditions there is a large variability in the available experimental data, rendering validation of the model difficult. The model suggests that the paracellular pathway of the RPE largely defines the total BRB permeability.

Conclusions

Our model is the first BRB model of its level and combines the present knowledge of the BRB barrier function. Furthermore, the model forms a platform for the future model development to be used for the design of new drugs and drug administration systems.

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Abbreviations

Å:

Angstrom (1 Å = 1 × 10−10 m)

AMD:

Age-related macular degeneration

BRB:

Outer blood-retinal barrier

BrM:

Bruch’s membrane

CE:

Choriocapillaris endothelium

Da:

Dalton (1 Da = 1.66 × 10−27 kg)

D 0 :

free diffusion coefficient (m2 s−1)

D eff,m :

Effective diffusion coefficient within the matrix m (m2 s−1)

D lat :

Lateral diffusion coefficient within the membrane (m2 s−1)

D ICL :

Effective diffusion coefficient within ICL (m2 s−1)

d ICL :

ICL thickness (m)

D OCL :

Effective diffusion coefficient within OCL (m2 s−1)

d OCL :

OCL thickness (m)

D m :

Diffusion coefficient within the matrix m (m2 s−1)

d lat,i :

Diffusion distance of ith part of the lateral diffusion pathway (m s−1)

d RPE :

RPE cell flat-to-flat diameter (m)

d TJp :

TJ pore separation (m)

f :

Adjusted fiber volume fraction

F m :

Hydrodynamic interactions in matrix m

h fen :

Fenestration height (m)

h LS :

Lateral space height (m)

H p (λ p ):

Pore hindrance factor

h pore :

Pore height (m)

h RPE :

RPE cell height (m)

H s (λ s ):

Slit hindrance factor

h slit :

Slit height (m)

h TJ :

TJ region height (m)

h TJs :

TJ strand height (m)

h TJss :

TJ strand separation (m)

ICL:

Inner collagenous layer

K mem :

Membrane distribution coefficient

k B :

Boltzmann’s constant (1.38 × 10−23 J K−1)

K D :

Octanol-water distribution coefficient

l cb :

Cell boundary length per unit area (m m−2)

M s :

Solute’s molecular mass (Da)

m :

Membrane size selectivity (Da−1)

n TJs :

TJ strand number

OCL:

Outer collagenous layer

P BRB :

BRB permeability coefficient (m s−1)

P BrM :

BrM permeability coefficient (m s−1)

P cyt :

Cytoplasm permeability coefficient (m s−1)

P CE :

CE permeability coefficient (m s−1)

P ICL :

ICL permeability coefficient (m s−1)

P lat :

Lateral diffusion transcellular permeability coefficient (m s−1)

P OCL :

OCL permeability coefficient (m s−1)

P lat,i :

Permeability coefficient of ith part of the lateral diffusion pathway (m s−1)

P LS :

Lateral space permeability coefficient (m s−1)

P mem :

Membrane permeability coefficient (m s−1)

P 0 mem :

Membrane permeability coefficient of a theoretical infinitely small molecule (m s−1)

P para :

Paracellular permeability coefficient (m s−1)

P pore :

Pore permeability coefficient (m s−1)

P RPE :

RPE permeability coefficient (m s−1)

P slit :

Slit permeability coefficient (m s−1)

P TJ :

TJ permeability coefficient (m s−1)

P TJl :

TJ leak pathway permeability coefficient (m s−1)

P TJp :

TJ pore pathway permeability coefficient (m s−1)

P TJs :

TJ strand permeability coefficient (m s−1)

P TJss :

Permeability coefficient of the space between TJ strands (m s−1)

P tr :

Transverse transcellular permeability coefficient (m s−1)

P trans :

Transcellular permeability coefficient (m s−1)

RPE:

Retinal pigment epithelium

r CF :

Collagen fibril radius (m)

r dia :

Diaphragm pore radius (m)

r f :

Fiber radius (m)

r PG :

Proteoglycan radius (m)

r pore :

Pore radius (m)

r* RPE :

Average RPE cell radius (m)

r s :

Solute molecule’s radius (m)

r TJp :

TJ pore radius (m)

S m :

Steric interactions in matrix m

T :

Absolute temperature (K)

TJ:

Tight junctions

τ RPE :

RPE lateral space tortuosity

W LS :

Lateral space half-width (m)

W slit :

Slit half-width (m)

α leak :

TJ leak parameter

ε lat,i :

Hindrance factor of ith part of the lateral diffusion pathway (m s−1)

ε LS :

Relative surface area of the lateral space

ε pore :

Relative surface area of the pores

ε slit :

Relative surface area of the slit

ε TJp :

Relative surface area of the TJ pores

φ CF,ICL :

Collagen volume fraction in ICL

φ CF,OCL :

Collagen volume fraction in OCL

Φ m :

Partition coefficient between the matrix m and solvent

φ f :

Fiber volume fraction

φ PG,ICL :

Proteoglycan volume fraction in ICL

φ PG,OCL :

Proteoglycan volume fraction in OCL

ε dia :

Relative surface area of the diaphragm pores

η:

Dynamic viscosity (Pa s)

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ACKNOWLEDGMENTS AND DISCLOSURES

The study was financially supported by the Academy of Finland (grant numbers 252225 and 260375) and TEKES—the Finnish Funding Agency for Technology and Innovation (grant number 718/31/2011).

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Authors and Affiliations

  1. BioMediTech, Tampere University of Technology, Tampere, Finland

    Aapo Tervonen, Iina Vainio, Soile Nymark & Jari Hyttinen

  2. Department of Electronics and Communications Engineering, Tampere University of Technology, Box 692, Tampere, 33101, Finland

    Aapo Tervonen, Iina Vainio, Soile Nymark & Jari Hyttinen

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  1. Aapo Tervonen
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Correspondence to Aapo Tervonen.

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Tervonen, A., Vainio, I., Nymark, S. et al. Prediction of Passive Drug Permeability Across the Blood-Retinal Barrier. Pharm Res 31, 2297–2311 (2014). https://doi.org/10.1007/s11095-014-1325-3

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  • DOI: https://doi.org/10.1007/s11095-014-1325-3

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