The advantage of using radiotracers for pre-clinical assays with conventional drugs: the case of meglumine antimoniate

The process of drug discovery and development requires substantial resources and time. A good understanding of the pharmacokinetics of the existing drugs could lead to a more successful strategy. The application of pharmacokinetic principles is one of the tools available for optimizing drug therapy, including drugs whose concentration-pharmacological response relationship is well established. Leishmaniases are mosquito-borne infectious diseases caused by protozoan parasites of the genus Leishmania. The mainstay of treatment remains pentavalent antimonial agents in the form of sodium stibogluconate (Pentostam®) or meglumine antimoniate (MA, Glucantime®). Despite the pharmacokinetics of pentavalent antimonials having been already reported, the available data are conflicting due to the different methodologies employed to measure antimony (Sb), the sample numbers, and the treatment schedules. In this review, we discussed the use of the radiolabelled compound to provide a sensitive and powerful tool to determine their pharmacokinetic properties. Radioisotopes of Sb were prepared to follow the biodistribution of MA and its liposomal formulations, also to evaluate the amount of Sb incorporated inside the liposomes. Samples of free MA and MA-liposomes in clean polypropylene tubes were placed together with Sb standards inside the aluminium container. Irradiations were carried out at a thermal neutron flux of 0.8 x 1012 n.cm-2.s-1 for 15 minutes inside the nuclear reactor. Two Sb tracers, ¹²²Sb and ¹²⁴Sb, were produced through the reactions ¹²¹Sb(n,γ)¹²²Sb and ¹²³Sb(n,γ)¹²⁴Sb. Studying the biodistribution of MA is easier and faster when the drug is radioactive when compared to conventional analytical techniques. Because there are no antimony radioisotopes commercially available, irradiating the MA was the best choice for the in vivo evaluation studies. The advantage of this procedure is that neutron irradiation of the stable antimony isotopes present in the MA formulation enables the detection and quantification of total antimony, but without distinguishing between the pentavalent and trivalent antimony species. We also found that there was no difference in the antileishmanial activity in the irradiated MA compared to the non-irradiated MA in both in vitro and in vivo evaluations. The use of radiotracers as a tool to evaluate the biodistribution of drugs in animal models is a feasible approach and these results could contribute to the development of new pharmacological studies using drug delivery systems for leishmaniases. This work emphasizes the importance of antimony pharmacokinetic profile in finding better therapeutic protocols as to its dosage, administration interval, and the duration of therapy. The use of radiotracer has great potential for improving the efficiency in the drug development process. (author)