Establishment of an In Vitro-In Vivo Correlation for Melanin Binding and the Extension of the Ocular Half-Life of Small Molecule Drugs

A large variety of drugs bind effectively to melanin and this binding influences their ocular pharmacokinetic and distribution profiles. We aimed to establish a correlation between in vitro melanin binding and in vivo ocular pharmacokinetics (PK). The extent of melanin binding in vitro was determined for a set of model drugs; binding kinetics and binding isotherms were generated and fitted to a mechanistic model to derive the drug-melanin binding parameters (Bmax, KD, kon and koff). In addition, in vitro ADME properties such as cellular permeability, P-glycoprotein mediated efflux, plasma protein binding and octanol partition coefficients were determined. Moreover, cellular uptake was measured in the non-pigmented ARPE-19 cells and in lightly pigmented human epidermal melanocytes (HEMn-LP). Finally, in vivo ocular PK studies were performed in albino and pigmented rats using intravenous injections. Substantial drug enrichment accompanied by a very long residence time was observed in pigmented ocular tissue...