Interaction of quinidine, disopyramide and metoprolol with melanin in vitro in relation to drug-induced ocular toxicity.
The aim of this work was to evaluate binding capacity of quinidine, disopyramide and metoprolol to melanin in vitro. The antiarrhythmics studied cause adverse reactions to the eye. Synthetic DOPA-melanin was used in the studies and a UV spectrophotometric method was employed to determine the drugs. The studies of the kinetics of the formation of quinidine-melanin, disopyramide-melanin and metoprolol-melanin complexes indicate that for all the complexes investigated the maximum time to reach reaction equilibrium is 24 h. Binding parameters, i.e., the numbers of independent binding sites and the association constants were determined on the basis of the Scatchard plots. An analysis of the binding curves obtained supports our conclusion that both strong (n1) and weak (n2) binding sites are involved in the formation of the complexes investigated. The total numbers of binding sites in synthetic DOPA-melanin complexes with quinidine, disopyramide and metoprolol were 0.525, 0.493 and 0.387 micromol/mg, respectively. The quinidine-melanin complex is characterized by greater stability (K1 = 3.00 x 10(5) M(-1), K2 = 1.75 x 10(3) M(-1)) in comparison with biopolymer complexes with disopyramide (K1 = 1.12 x 10(4) M(-1), K2 = 6.04 x 10(2) M(-1)) and metoprolol (K1 = 1.42 x 10(4) M(-1), K2 = 7.89 x 10(2) M(-1)). The ability of these drugs to form complexes with melanin in vitro may be one of the reasons for their ocular toxicity in vivo, as a result of their accumulation in melanin in the eye.
Buszman
E
E
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Silesia, Sosnowiec, Poland. ebuszman@slam.katowice.pl
Rózańska
R
R
D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D004295:Dihydroxyphenylalanine / Q000737:chemistry; D004206:Disopyramide / Q000737:chemistry* / Q000633:toxicity; D005128:Eye Diseases / Q000139:chemically induced; D007700:Kinetics; D008543:Melanins / Q000138:chemical synthesis / Q000737:chemistry*; D008790:Metoprolol / Q000737:chemistry* / Q000633:toxicity; D011802:Quinidine / Q000737:chemistry* / Q000633:toxicity; D013056:Spectrophotometry, Ultraviolet
D000889:Anti-Arrhythmia Agents; D008543:Melanins; D004295:Dihydroxyphenylalanine; D008790:Metoprolol; D004206:Disopyramide; D011802:Quinidine