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Binding of dorzolamide and its metabolite, N-deethylated dorzolamide, to human erythrocytes in vitro

T Hasegawa, K Hara and S Hata

Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., Saitama, Japan.

Dorzolamide, previously known as MK-507, is a novel topical carbonic anhydrase (CA) inhibitor. The uptake and binding of dorzolamide and its N-deethylated metabolite to human erythrocytes were studied in vitro. Dorzolamide and N-deethylated dorzolamide were preferentially taken up by the erythrocytes, and the uptake of dorzolamide by erythrocytes was found to be much faster than that of N-deethylated dorzolamide. When 20 or 200 microM dorzolamide was incubated with human erythrocytes, 98% or 71% of the drug was taken up by the erythrocytes, respectively. Similarly, using 20 or 200 microM N-deethylated dorzolamide, 99.7% or 75% of the drug was taken up by the erythrocytes, respectively. These results indicate that human erythrocytes contain proteins that bind to dorzolamide and N-deethylated dorzolamide, and the binding of these proteins is saturable. The results of the in vitro binding study suggest that presence of at least three kinds of binding site for dorzolamide in human erythrocytes. One of the binding sites for dorzolamide was characterized by extremely high affinity (Kd = 0.0011 microM) and low capacity (Bmax = 16.1 microM), corresponding to CA-II. Another binding site was characterized by low affinity (Kd = 2.8 microM) and high capacity (Bmax = 117.1 microM), corresponding to CA-I. The third one was a nonspecific binding. The binding of N-deethylated dorzolamide to human CA-I and CA-II was competitively inhibited by dorzolamide, indicating that these compounds bind to the same binding site on CAs. In each other's presence, most of dorzolamide in erythrocytes binds to CA-II, whereas the N-deethylated metabolite mainly binds to CA-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 22, Issue 3, pp. 377-382, 05/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




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