Melarsoprol is the only currently available
drug for treatment of the late stage of
African trypanosomiasis (sleeping sickness). Unfortunately, the
arsenic-containing
drug causes serious side effects, for which the mechanisms have not been elucidated so far. This investigation describes the study of the
melarsoprol biotransformation processes by electrochemical (EC) techniques. Based on EC, potential oxidation reactions of
melarsoprol are examined. Moreover, the reactivity of
melarsoprol, its metabolite
melarsen oxide, and their oxidation products toward the tripeptide
glutathione and the
proteins hemoglobin and
human serum albumin is evaluated. The combination of different analytical techniques allows the identification as well as the quantification of the biotransformation products. The hyphenation of liquid chromatography (LC) and electrospray ionization mass spectrometry (ESI-MS) is applied for identification and structure elucidation, which implies the determination of exact masses and fragmentation patterns. For the selective detection of
arsenic containing metabolites, LC coupled to inductively coupled plasma mass spectrometry is utilized. Based on the obtained data, the oxidative biotransformation of
melarsoprol can be predicted, revealing novel species which have been suspected, but not been identified up to now. The results of the
protein studies prove that
melarsen oxide, the active derivative of
melarsoprol, strongly binds to human
hemoglobin and forms different adducts via the free cysteinyl groups of the
hemoglobin α- and β-chain.