RELEVANCE OF DRUG-MELANIN INTERACTIONS TO OCULAR PHARMACOLOGY AND TOXICOLOGY

In melanocytes, the biosynthesis of L-dopa derived indole polymer, mel anin, is accelerated by tyrosinase and related enzymes. The brown to b lack pigment is characterized by a stable free-radical property. In hu mans, a pigment dependent slow onset of ocular actions of ephedrine, a tropine, cocaine, pilocarpine and related medications was observed. Ex tensive accumulation of drugs by melanin appears to be the most import ant factor governing the long term therapeutic/toxicological activitie s. Drugs crossing placental circulation are localized in the mouse fet al eye. Thus, drugs exhibit a high binding capacity for melanin contai ning tissues. Studies on synthetic melanin and melanin granules also i ndicated a high binding capacity of many therapeutic classes of drugs, including psychotropics. In addition to the liposoluble property of t he molecule, there is a definite relationship between chemical structu re and the affinity of drugs for melanin. For example, the affinity of chlorpromazine for melanin is higher than that of chlorprothixene. NM R studies, with soluble melanins indicate that there is a steric prefe rence among ephedrine enantiomers. A high binding capacity indicates t hat more than two molecules of (-)-ephedrine may complex with one indo le unit of melanin. Ocular drug development calls for the study of qua litative and quantitative aspects of drug-melanin interaction.