The melanin binding of bisoprolol and its toxicological relevance

Unexpectedly high accumulations of bisoprolol were detected in iris and ciliary body and in retina+choroid of beagles after 4 weeks of conjunctival and oral administration. This phenomenon gave reason to assume that these high concentrations in the pigmented structures of the eye might be related to melanin binding. According to literature a series of drugs, e.g. chloroquine, rifampicine, chlorpromazine, benzodiazepines, and also beta-adrenoceptor antagonists exhibit melanin-binding properties. By means of autoradiography it could be demonstrated in pigmented mice that after iv and po administration 14C-labelled bisoprolol was selectively bound to the melanin-containing parts of the eye, irrespective of the mode of administration. Since the melanin-bound radioactivity could be extracted from the eye of mice and was eliminated with a t1/2 of approx. 7 days, the melanin binding of bisoprolol is considered to be reversible. Other beta-blocking agents like timolol and befunolol used already for a long time in the therapy of glaucoma have been reported to bind specifically to the melanin of the eye, and show comparable long half-lives, similar to bisoprolol. Usually, autoradiographic studies on drug distribution are performed with albino animals. This leads to a lack of information on melanin binding and may result in misinterpretation concerning the retention of substances, especially in pigmented compartments of the eye. Therefore, in autoradiographic studies of new investigational drugs during preclinical development, one should use both pigmented and albino animals.