Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate

Abstract

Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 >> 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies.

Effects of in utero and lactational exposure to SbV on rat neurobehavioral development and fertility

“…To determine the total Sb by solution nebulization ICP-MS, the whole blood and milk samples were analyzed after digestion with HNO 3 (Merck, Darmstadt, Germany), purification by two cycles of sub-boiling distillation and an appropriate dilution with MilliQ (Millipore, Bedford, MA, USA) purified water. The tissue samples were lyophilized and wet-ashed with HNO 3 -H 2 O 2 in closed polyethylene tubes as previously reported [8,13]. The diluted digest was then analyzed by ICP-MS using the quantitative external calibration method.…”

“…6 (6-9) 7 (6-9) 6 (5-9) 6 (6-9) Incisor eruption 12 ( 6 (3-11.5) 5.5 (4-8) 5.5 (3-7) Negative geotaxis 5.25 (4.5-9) 6 (4.5-8) 6 (4-9.5) 6 (4-10.5) Palmar grasp 8 (7-10) 8 (6-10) 7.25 (6-11) 8 (4-9.5) Auditory startle response 13 (12)(13)(14) 13 (12)(13)(14) 13 (12)(13)(14) 13 (12.5-14) Free-fall righting 18 (16)(17)(18)(19) 18 (15.5-20) 18 (16)(17)(18)(19)(20) 17.75 (16)(17)(18)(19)(20) The data are shown as the median and range (minimum-maximum) of the day on which landmarks appeared or reflexes were acquired. The litter was the statistical unit of analysis.…”

“…In the former group (PND 15), however, the lactating females were milked 24 h after the last dose of MA, while the latter group (PND 19) was milked 48 h after the drug injection and 24 h after the pups had been removed from their dam's cage (Table 8). Previous kinetic studies have shown that most of the Sb contained in a single dose of MA is eliminated from the maternal organism during the first 12 h after injection (fast elimination phase); therefore, only residual levels are found in the blood afterwards (slow elimination phase) [13]. One can expect therefore that the milk produced by the mammary glands during the first 24 h after MA injection (including the initial period of fast elimination phase) contains more Sb than the milk that was produced between 24 h and 48 h after the injection, a period that corresponds to the terminal slow elimination phase only.…”

“…In humans [6,8], monkeys [9], dogs [10], mice [11], hamsters [12] and rats [13,14], the decreases in the Sb blood levels with time after Sb V drug injection fit a two-compartment (or even multicompartment) kinetic model. The slow elimination phase of the bi-exponential decline of the Sb blood levels has a half-life longer than 24 h. This fact explains the therapeutic and toxic effects resulting from the repeated administration of doses administered at 24-h intervals (generally a three-week course of treatment) [6,9,13].…”

“…The slow elimination phase of the bi-exponential decline of the Sb blood levels has a half-life longer than 24 h. This fact explains the therapeutic and toxic effects resulting from the repeated administration of doses administered at 24-h intervals (generally a three-week course of treatment) [6,9,13]. Most of the Sb given as MA is rapidly eliminated (via urine) within 6-12 h after drug injection; therefore, very low (nadir) levels are found in the blood 24 h after dosing.…”