The melanin binding of drugs and its implications (pdf)
affinity of drugs to melanin and the resultant physiological effects
on the organism
of drugs to melanin is causative for a multitude of
(patho)physiological or toxic effects in biological systems:
particular imortance is for example the affinity of antimalarial
drugs in long-term treatment (Larsson, 1993). The potentially
antimalarial chloroquine is for example detectable in considerable
the retina of laboratory animals even one year after a single i.v.
(Lindquist and Ullberg, 1972). Its harmful effects, like the incidence
chorioretinopathy, may be explained by its accumulation in retinal
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
especially if therapeutics shall selectively act on melanin-containing
This is the case in the treatment of diseases accompanied with melanin
hyperpigmentation. An especially fatal example for these diseases may
malignant melanoma. A selective accumulation of a respective drug in
melanin-containing cells would considerably reduce the degree of
Physiological effects and adverse reactions caused by binding of
pharmacologically active substances to melanin should be considered
the phase of development!
causal relationship between adverse reactions of drugs and their
affinity to melanin should become obvious!
B.S., 1993, Interaction between chemicals and
melanin, Pigment Cell Res 6, 127.
Lindquist, N.G. and S. Ullberg, 1972, The melanin affinity of
chlorpromazine studied by whole body autoradiography, Acta Pharmacol
(Copenh) 2:Suppl, 1.
Examples of pathophysiologic relevances of melanin
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
movement disorders associated with long-term or high-dose treatment
antipychotic drugs. Tardive dyskinesia are often observed in older
after termination of or dose-reduction in treatment with neuroleptics.
Retinal damage is the most important hazard from light. The protective
mechanism of melanin in the retinal pigment epithelium mainly consists
absorption of UV-induced radicals. A loss of this radical
scavenger properties of
melanin results in retinal damages.
drugs or harmful substances may also result in damages of
the retina, a prominent example is the chorioretinopathy induced by
use of native instead of radiolabelled substances
Besides the classical approaches like binding experiments or
dialysis, IBAM offers a self developed and patented assay based on
chromatography for the determination of melanin affinities of drugs.
The advantages of such an affinity chromatographic approach are:
- time and cost consuming radiolabelling is not necessary
- the formation of metabolites can chromatographically be detected, a
simple radioassay does not allow this.
recording of binding curves for several substances to melanin with
IBAM’s affinity chromatographic approach allows a clear
quantification of the melanin affinities of these substances
(Knörle et al.,
1998). Binding curves are obtained by plotting the retention (V-V0)
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
table together with the respective 95% confidence intervals.
Knörle, R., E. Schniz
and T.J. Feuerstein,
1998, Drug accumulation in melanin: An affinity chromatographic study,
J. Chromatography B, 714, 171.