Binding of drugs to melanin

back


The melanin binding of drugs and its implications (pdf)







The affinity of drugs to melanin and the resultant physiological effects on the organism

 
Binding of drugs to melanin is causative for a multitude of (patho)physiological or toxic effects in biological systems:

Of particular imortance is for example the affinity of antimalarial drugs in long-term treatment (Larsson, 1993). The potentially retinotoxic antimalarial chloroquine is for example detectable in considerable amouts in the retina of laboratory animals even one year after a single i.v. injection (Lindquist and Ullberg, 1972). Its harmful effects, like the incidence of a chorioretinopathy, may be explained by its accumulation in retinal melanin and long-lasting release from this depot.

Besides the undesired accumulation in melanin-pigmented tissues, a high affinity of drugs to melanin may even be relevant for their specific action, especially if therapeutics shall selectively act on melanin-containing tissues. This is the case in the treatment of diseases accompanied with melanin hyperpigmentation. An especially fatal example for these diseases may be the malignant melanoma. A selective accumulation of a respective drug in melanin-containing cells would considerably reduce the degree of adverse reactions.

Physiological effects and adverse reactions caused by binding of pharmacologically active substances to melanin should be considered already in the phase of development!

The causal relationship between adverse reactions of drugs and their affinity to melanin should become obvious!


References:

Larsson, B.S., 1993, Interaction between chemicals and melanin, Pigment Cell Res 6, 127.
Lindquist, N.G. and S. Ullberg, 1972, The melanin affinity of chloroquine and chlorpromazine studied by whole body autoradiography, Acta Pharmacol Toxicol (Copenh) 2:Suppl, 1.



Examples of pathophysiologic relevances of melanin binding:

Tardive dyskinesia:
The occurence of tardive dyskinesia is closely related to the melanin affinities of the causative neuroleptics
(Lyden et al., 1982; Salazar et al., 1978). Tardive dyskinesia are involuntary extrapyramidal movement disorders associated with long-term or high-dose treatment with antipychotic drugs. Tardive dyskinesia are often observed in older patients after termination of or dose-reduction in treatment with neuroleptics.

Retinal damages
Retinal damage is the most important hazard from light. The protective mechanism of melanin in the retinal pigment epithelium mainly consists in the absorption
of UV-induced radicals. A loss of this radical scavenger properties of melanin results in retinal damages.

Melanin-bound drugs or harmful substances may also result in damages of the retina, a prominent example is the chorioretinopathy induced by melanin-bound chloroquine.


Our methods

Besides the classical approaches like binding experiments or equilibrium dialysis, IBAM offers a self developed and patented assay based on affinity chromatography for the determination of melanin affinities of drugs. 

The advantages of such an affinity chromatographic approach are:

- use of native instead of radiolabelled substances
- time and cost consuming radiolabelling is not necessary
- the formation of metabolites can chromatographically be detected, a simple radioassay does not allow this.


The recording of binding curves for several substances to melanin with IBAM’s affinity chromatographic approach allows a clear discrimination and quantification of the melanin affinities of these substances (Knörle et al., 1998). Binding curves are obtained by plotting the retention (V-V0) versus the particle number applied N0. Analysis of the binding curve is performed using non-linear modelling. The function (V-V0)=D+1/N0c allows a very close fit of the curve to the data points. Non of the classical approaches results in such a good fit. The melanin affinities of several drugs are given in the following table together with the respective 95% confidence intervals.




drug c D
Chloroquine 0,37 [0,36; 0,38] -171,3 [-198,3; -144,1]
Haloperidol 0,27 [0,26; 0,28] -51,6 [-69,2; -33,5]
Desipramine 0,18 [0,17; 0,18] -10,0 [-10,5;-9,6]
Sulpirid 0,15 [0,15; 0,16] -4,1 [-4,8; -3,3]
Flunitrazepam 0,08 [0,07; 0,08] -2,0 [-2,4; -1,7]

Reference:

Knörle, R., E. Schniz and T.J. Feuerstein, 1998, Drug accumulation in melanin: An affinity chromatographic study, J. Chromatography B, 714, 171.