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Comparative Study
. 2011 Jul 23;52(8):5387-99.
doi: 10.1167/iovs.10-6233.

Sclera-choroid-RPE transport of eight β-blockers in human, bovine, porcine, rabbit, and rat models

Rajendra S Kadam  1 , Narayan P S Cheruvu, Henry F Edelhauser, Uday B Kompella
Affiliations
Comparative Study

Sclera-choroid-RPE transport of eight β-blockers in human, bovine, porcine, rabbit, and rat models

Rajendra S Kadam et al. Invest Ophthalmol Vis Sci. .

Retraction in

Abstract

Purpose: To determine the influence of drug lipophilicity, ocular pigmentation, and species differences on transscleral solute transport.

Methods: The transport of eight β-blockers across excised sclera/sclera-choroid-RPE (SCRPE) of albino rabbit, pigmented rabbit, human, porcine, and bovine eyes was determined over 6 hours. The ex vivo transscleral β-blocker transport to the vitreous at the end of 6 hours was determined in euthanatized, pigmented Brown Norway rats. The thicknesses of the sclera and SCRPE and the melanin content in choroid-RPE (CRPE) were measured to determine whether species differences in drug transport can be explained on this basis.

Results: Solute lipophilicity inversely correlated with the SCRPE cumulative percentage of transport in all species (R(2) ≥ 0.80). The CRPE impeded the SCRPE transport of all β-blockers (51%-64% resistance in the rabbits; 84%-99.8% in the bovine and porcine eyes) more than the sclera, with the impedance increasing with lipophilicity. SCRPE transport followed the trend albino rabbit > pigmented rabbit > human > porcine > bovine, and a cross-species comparison showed good Spearman's rho correlation (R(2) ≥ 0.85). Bovine (R(2) = 0.84), porcine (R(2) = 0.84), and human (R(2) = 0.71) SCRPE transport was more predictive than that in the rabbit models (R(2) = 0.60-0.61) of transscleral solute transport to the vitreous in rats. The CRPE concentrations were higher in pigmented rabbits than in albino rabbits. The melanin content of the CRPE exhibited the trend albino rabbit ≪ pigmented rabbit < porcine ∼ bovine < rat. Normalization to scleral thickness abolished the species differences in scleral transport. Normalization to SCRPE thickness and melanin content significantly reduced species differences in SCRPE transport.

Conclusions: Owing to the presence of pigment and drug binding, choroid-RPE is the principal barrier to transscleral β-blocker transport, with the barrier being more significant for lipophilic β-blockers. Although different in magnitude between species, sclera/SCRPE transport can be correlated between species. Tissue thickness accounts for the species differences in scleral transport. Differences in tissue thickness and melanin content largely account for the species differences in SCRPE transport.

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Figures

Figure 1.
Figure 1.
Scleral transport of β-blockers in various species. The data show cumulative percentages of transport of β-blockers across excised bovine, porcine, pigmented rabbit, and albino rabbit sclera devoid of CRPE. Solid line: transport before normalization for scleral thickness; dashed line: transport after normalization by multiplying with scleral thickness in mm. The data are expressed as the mean ± SD for n = 6.
Figure 2.
Figure 2.
The species differences in β-blocker transport across the sclera were abolished after normalization for scleral thickness. The cumulative percentage of transport at the end of 6 hours (A) before and (B) after normalization for tissue thickness. The apparent permeability coefficients (C) before and (D) after normalization for tissue thickness. The results are expressed as the mean ± SD for n = 6.
Figure 3.
Figure 3.
SCRPE transport of β-blockers in various species. Data show the cumulative percentages of transport of β-blockers across bovine, porcine, human, pigmented rabbit, and albino rabbit SCRPE. Solid line: the transport before normalization for SCRPE thickness. Dashed line: transport after normalization by multiplying with SCRPE thickness in mm. The data are expressed as the mean ± SD for n = 6.
Figure 4.
Figure 4.
The species differences in β-blocker transport across the SCRPE was reduced but remained after normalization for SCRPE thickness and pigment content in the CRPE. The cumulative percentage of transport at the end of 6 hours (A) before normalization, (B) after normalization for SCRPE thickness, and (C) after normalization for SCRPE thickness and melanin content in the CRPE. The results are expressed as the mean ± SD for n = 6.
Figure 5.
Figure 5.
The cumulative percentage of transport across the sclera and SCRPE declined with the increase in drug lipophilicity in the various species. Correlation of the cumulative percentages of β-blocker transport at the end of 6 hours with the log P in (A) albino rabbit, (B) pigmented rabbit, (C) human, (D) porcine, and (E) bovine tissues. The results are expressed as the mean ± SD for n = 6.
Figure 6.
Figure 6.
Melanin content in the sclera and CRPE of albino rabbit, pigmented rabbit, porcine, bovine, and BN rat eyes. All measures except those in the rat tissues were made in the present study. The rat tissue measurements are reported elsewhere by our group. The data are expressed as the mean ± SD for n = 4. †Significantly different from the CRPE in the same species. Significantly different from *albino rabbit CRPE and ‡pigmented rabbit CRPE.
Figure 7.
Figure 7.
The cross-species correlation of β-blocker transport in the (A) sclera and (B) SCRPE. Data are expressed as the mean for n = 6. Rho (ρ), Spearman's rho correlation coefficient. Scleral data were normalized to the tissue thickness and the SCRPE data were normalized to the tissue thickness and the CRPE melanin content.
Figure 8.
Figure 8.
β-Blocker accumulation in the (A) sclera and (B) CRPE at the end of a 6-hour transport study in various species. The β-blockers are arranged from low to high log P. The results are expressed as the mean ± SD for n = 6.
Figure 9.
Figure 9.
An increase in lipophilicity did not result in enhanced drug transport to the vitreous in euthanatized BN rats. Shown are rat ocular tissue concentrations of β-blockers at the end of 6 hours after periocular administration of a solution of eight β-blockers in phosphate-buffered saline. The β-blockers are arranged from low to high log P. The data are expressed as the mean ± SD for n = 4.
Figure 10.
Figure 10.
In vitro transport across human, porcine, and bovine SCRPE correlated better with ex vivo vitreal drug delivery in BN rats than that in the rabbit. Shown is the correlation of the ex vivo vitreal concentration of β-blockers at the end of 6 hours in euthanatized BN rats after periocular administration with in vitro cumulative percentages of transport at the end of 6 hours across the SCRPE in the various species. The results are expressed as the mean ± SD (n = 4) for ex vivo vitreal concentration and the mean ± SD (n = 6) for in vitro transport data.
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Comment in

  • Findings of Research Misconduct.
    [No authors listed] [No authors listed] Fed Regist. 2018 Dec 6;83(234):62875. Fed Regist. 2018. PMID: 30556543 Free PMC article. No abstract available.

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