title: Biodistribution of meglumine antimoniate in healthy and Leishmania (Leishmania) infantum chagasi-infected BALB/c mice.
abstract: Pentavalent antimonials such as meglumine antimoniate (MA) are the primary treatments for leishmaniasis, a complex disease caused by protozoan parasites of the genus Leishmania . Despite over 70 years of clinical use, their mechanisms of action, toxicity and pharmacokinetics have not been fully elucidated. Radiotracer studies performed on animals have the potential to play a major role in pharmaceutical development. The aims of this study were to prepare an antimony radiotracer by neutron irradiation of MA and to determine the biodistribution of MA in healthy and Leishmania (Leishmania) infantum chagasi-infected mice. MA (Glucantime®) was neutron irradiated inside the IEA-R1 nuclear reactor, producing two radioisotopes, ¹²²Sb and ¹²⁴Sb, with high radionuclidic purity and good specific activity. This irradiated compound presented anti-leishmanial activity similar to that of non-irradiated MA in both in vitro and in vivo evaluations. In the biodistribution studies, healthy mice showed higher uptake of antimony in the liver than infected mice and elimination occurred primarily through biliary excretion, with a small proportion of the drug excreted by the kidneys. The serum kinetic curve was bi-exponential, with two compartments: the central compartment and another compartment associated with drug excretion. Radiotracers, which can be easily produced by neutron irradiation, were demonstrated to be an interesting tool for answering several questions regarding antimonial pharmacokinetics and chemotherapy.
authors.affiliation: Centro de Biotecnologia, Instituto de Pesquisas Energéticas e Nucleares, Comissão Nacional de Energia Nuclear, São Paulo, SP, Brasil. samantaborborema@gmail.com
authors.forename: Samanta Etel Treiger
authors.initials: SE
authors.lastname: Borborema
authors.forename: João Alberto
authors.initials: JA
authors.lastname: Osso
authors.forename: Heitor Franco de
authors.initials: HF
authors.lastname: Andrade
authors.forename: Nanci do
authors.initials: Nd
authors.lastname: Nascimento
mesh_terms: D000818:Animals; D000965:Antimony; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics* / Q000528:radiation effects; D006224:Cricetinae; D005260:Female; D018314:Leishmania infantum; D007896:Leishmaniasis; D008536:Meglumine / Q000493:pharmacokinetics* / Q000528:radiation effects; D000077485:Meglumine Antimoniate; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000528:radiation effects; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000965:Antimony
references.citation: Ind Med Gaz. 1950 Sep;85(9):388-91
references.pmid: 14794190
references.citation: Antimicrob Agents Chemother. 2005 Mar;49(3):1076-80
references.pmid: 15728905
references.citation: Ann Trop Med Parasitol. 1992 Feb;86(1):35-40
references.pmid: 1319700
references.citation: J Pharm Pharmacol. 1988 May;40(5):370-3
references.pmid: 2899637
references.citation: Rev Inst Med Trop Sao Paulo. 1987 May-Jun;29(3):131-6
references.pmid: 3324279
references.citation: Curr Pharm Des. 2001 Dec;7(18):1945-66
references.pmid: 11772359
references.citation: Drug Resist Updat. 2004 Aug-Oct;7(4-5):257-66
references.pmid: 15533763
references.citation: Int J Antimicrob Agents. 2011 Oct;38(4):341-7
references.pmid: 21783345
references.citation: J Pharmacol Exp Ther. 1946 Oct;88(2):162-72
references.pmid: 20274538
references.citation: Lancet. 1980 Aug 2;2(8188):226-9
references.pmid: 6105394
references.citation: Antimicrob Agents Chemother. 1998 May;42(5):1076-82
references.pmid: 9593130
references.citation: Adv Drug Deliv Rev. 2001 May 16;48(1):115-36
references.pmid: 11325479
references.citation: Trans R Soc Trop Med Hyg. 1988;82(1):69-72
references.pmid: 2845611
references.citation: J Immunol Methods. 1986 Nov 6;93(2):157-65
references.pmid: 3490518
references.citation: Int J Antimicrob Agents. 2000 Feb;13(4):243-8
references.pmid: 10755238
references.citation: Antimicrob Agents Chemother. 1995 Feb;39(2):516-9
references.pmid: 7726524
references.citation: Res Vet Sci. 1994 Mar;56(2):144-50
references.pmid: 8191002
references.citation: Expert Opin Drug Deliv. 2010 Dec;7(12):1343-58
references.pmid: 21029028
references.citation: Clin Pharmacokinet. 2002;41(10):751-90
references.pmid: 12162761
references.citation: Am J Trop Med Hyg. 1988 Jul;39(1):41-5
references.pmid: 2840834
references.citation: N Engl J Med. 2007 Sep 6;357(10):1018-27
references.pmid: 17804846
references.citation: Comp Immunol Microbiol Infect Dis. 2004 Sep;27(5):305-18
references.pmid: 15225981
references.citation: PLoS One. 2012;7(5):e35671
references.pmid: 22693548
references.citation: Ann Trop Med Parasitol. 1994 Feb;88(1):37-41
references.pmid: 8192513
references.citation: Vet Rec. 1996 Feb 24;138(8):181-3
references.pmid: 8677619
references.citation: Antimicrob Agents Chemother. 1993 Sep;37(9):1842-6
references.pmid: 8239593
references.citation: Rev Soc Bras Med Trop. 1996 Sep-Oct;29(5):461-5
references.pmid: 8966310
references.citation: Antimicrob Agents Chemother. 1995 Jun;39(6):1234-9
references.pmid: 7574507