Interaction of chlorpromazine, fluphenazine and trifluoperazine with ocular and synthetic melanin in vitro.
The aim of this study was to examine in vitro the binding capacity of three phenothiazine derivatives--chlorpromazine, fluphenazine and trifluoperazine--causing adverse effects in the eye structures, to natural melanin isolated from pig eyes as well as to synthetic DOPA-melanin used as a model polymer. The amount of drug bound to melanin was determined by UV spectrophotometry. The analysis of results for the kinetics of drug-melanin complex formation showed that the amount of drug bound to melanin increases with increasing initial drug concentration and longer incubation time, attaining an equilibrium state after about 24 h. Binding parameters, i.e. the number of binding sites (n) and association constants (K), were determined on the basis of Scatchard plots. For neuroleptic-ocular melanin and neuroleptic-DOPA-melanin complexes two classes of independent binding sites were found, with association constants K1 approximately 10(4) and K2 approximately 10(2) M (-1) for chlorpromazine and fluphenazine complexes, and K1 approximately 10(5) and K2 approximately 10(3) M(-1) for trifluoperazine complexes. The numbers of strong (n1) and weak (n2) binding sites indicate lower affinity of the drugs examined to ocular melanin compared with DOPA-melanin. The ability of chlorpromazine, fluphenazine and trifluoperazine to interact with melanin, especially the ocular melanin, in vitro is discussed in relation to the ocular toxicity of these drugs in vivo.
Buszman
E
E
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Silesia, Sosnowiec, Poland. ebuszman@slam.katowice.pl
Beberok
A
A
Rózańska
R
R
Orzechowska
A
A
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry*; D002746:Chlorpromazine / Q000737:chemistry*; D005123:Eye / Q000737:chemistry*; D005476:Fluphenazine / Q000737:chemistry*; D007202:Indicators and Reagents; D007700:Kinetics; D008543:Melanins / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013552:Swine; D014268:Trifluoperazine / Q000737:chemistry*
D014150:Antipsychotic Agents; D007202:Indicators and Reagents; D008543:Melanins; D014268:Trifluoperazine; D005476:Fluphenazine; D002746:Chlorpromazine