Investigations of the metabolites of the trypanocidal drug melarsoprol

Background: Melarsoprol remains the first-choice drug for trypanosomiasis ( human African sleeping sickness). To contribute to the sparse pharmacologic data and to better understand the cause of the frequent serious adverse re actions, we investigated the metabolism of this 50-year-old organoarsenic c ompound. Results: The half-life of melarsoprol determined by HPLC was <1 hour compar ed with 35 hours determined by bioassay and atomic absorption spectroscopy, indicating re existence of active metabolites. One metabolite, melarsen ox ide, was identified by ultraviolet HPLC after incubation of molarsoprol Wit h microsomes, The maximum plasma concentration of melarsenoxide was reached 15 minutes after administration; the clearance was 21.5 mL/min/kg and the half-life of free melarsen oxide was 3.9 hours, Either melarsen oxide or a yet-undiscovered active metabolite is irreversibly bound to proteins, as sh own by ultrafiltration, precipitation experiments, and atomic absorption sp ectroscopy. Because of the poor pharmaceutical properties of melarsoprol, t he therapeutic potential of melarsen oxide was investigated. In a rodent mo del of acute infection, 20 of 20 mice were cued (0.1 to 1 mg/kg intravenous ly or 2.2 mg/kg intraperitoneally), In a rodent model of central nervous sy stem infection, five of six mice survived for more than 180 days (5 mg/kg i ntravenously), indicating a sufficient melarsen oxide penetration across th e blood-brain barrier. Conclusion: The prospects for the future of trypanosomiasis treatment are d eplorable. Investigations on the improvement of the use of the old drugs ar e therefore required. The results of this study. may build a basis for furt her research on the cause of severe adverse reactions.