Pharmacokinetics of neutron-irradiated meglumine antimoniate in Leishmania amazonensis-infected BALB/c mice

 

Samanta Etel Treiger Borborema^1  2, João Alberto Osso Junior ³, Heitor Franco de Andrade Junior ⁴, Nanci do Nascimento^1 †

 

1 Center for Biotechnology, Nuclear and Energy Research Institute, São Paulo, SP, Brazil.

2 Center for Parasitology and Mycology, Adolfo Lutz Institute, São Paulo, SP, Brazil.

3 Center for Radiopharmacy, Nuclear and Energy Research Institute, São Paulo, SP, Brazil.

4 Laboratory of Protozoology, São Paulo Tropical Medicine Institute, University of São Paulo (IMTSP/USP) São Paulo, SP, Brazil.

 

ABSTRACT

Background:

Cutaneous leishmaniasis (CL) is a parasitic disease caused by the protozoan Leishmania spp. Pentavalent antimonial agents have been used as an effective therapy, despite their side effects and resistant cases. Their pharmacokinetics remain largely unexplored. This study aimed to investigate the pharmacokinetic profile of meglumine antimoniate in a murine model of cutaneous leishmaniasis using a radiotracer approach.

 

Methods:

Meglumine antimoniate was neutron-irradiated inside a nuclear reactor and was administered once intraperitoneally to uninfected and L. amazonensis-infected BALB/c mice. Different organs and tissues were collected and the total antimony was measured.

 

Results:

Higher antimony levels were found in infected than uninfected footpad (0.29% IA vs. 0.14% IA, p = 0.0057) and maintained the concentration. The animals accumulated and retained antimony in the liver, which cleared slowly. The kidney and intestinal uptake data support the hypothesis that antimony has two elimination pathways, first through renal excretion, followed by biliary excretion. Both processes demonstrated a biphasic elimination profile classified as fast and slow. In the blood, antimony followed a biexponential open model. Infected mice showed a lower maximum concentration (6.2% IA/mL vs. 11.8% IA/mL, p = 0.0001), a 2.5-fold smaller area under the curve, a 2.7-fold reduction in the mean residence time, and a 2.5-fold higher clearance rate when compared to the uninfected mice.

 

Conclusions:

neutron-irradiated meglumine antimoniate concentrates in infected footpad, while the infection affects antimony pharmacokinetics.

 

Keywords: cutaneous leishmaniasis; meglumine antimoniate; pharmacokinetics; biodistribution; antimony; radioisotope

 

Received: May 03, 2018.

Accepted: October 17, 2018.

 

Correspondence: samantaborborema@gmail.com

 

^† In Memoriam

 

Competing interests Not apllicable.

 

Authors' contributions SETB, JAOJ, HFAJ and NN designed the study. SETB performed the data acquisition. SETB, JAOJ, HFAJ and NN analyzed data. SETB drafted the article. SETB, JAOJ, HFAJ and NN read and approved the final manuscript.