title: Sclera-choroid-RPE transport of eight β-blockers in human, bovine, porcine, rabbit, and rat models.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Kadam
authors.forename: Narayan P S
authors.initials: NP
authors.lastname: Cheruvu
authors.forename: Henry F
authors.initials: HF
authors.lastname: Edelhauser
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001692:Biological Transport; D002417:Cattle; D002829:Choroid / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008875:Middle Aged; D010539:Permeability; D011817:Rabbits; D051381:Rats; D011914:Rats, Inbred BN; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D012590:Sclera / Q000378:metabolism*; D013045:Species Specificity; D013552:Swine; D053719:Tandem Mass Spectrometry
chemical_list: D000319:Adrenergic beta-Antagonists; D008543:Melanins