Disposition of Antimony in Rhesus Monkeys Infected withLeishmania braziliensisand Treated with Meglumine Antimoniate

Abstract

Antimony (Sb) disposition and toxicity was evaluated in Leishmania braziliensis-infected monkeys (Macaca mulatta) treated with a 21-d course of low (LOW) or standard (STD) meglumine antimoniate (MA) dosage regimens (5 or 20 mg Sb(V)/kg body weight/d im). Antimony levels in biological matrices were determined by inductively coupled plasma mass spectrometry (ICPMS), while on-line ion chromatography coupled to ICPMS was used to separate and quantify Sb species in plasma. Nadir Sb levels rose steadily from 19.6 ± 4 and 65.1 ± 17.4 ng/g, 24 h after the first injection, up to 27.4 ± 5.8 and 95.7 ± 6.6 ng/g, 24 h after the 21st dose in LOW and SDT groups, respectively. Subsequently, Sb plasma levels gradually declined with a terminal elimination phase half-life of 35.8 d. Antimony speciation in plasma on posttreatment days 1-9 indicated that as total Sb levels declined, proportion of Sb(V) remained nearly constant (11-20%), while proportion of Sb(III) rose from 5% (d 1) to 50% (d 9). Plasma [Sb]/erythrocyte [Sb] ratio was >1 until 12 h after dosing and reversed thereafter. Tissue Sb concentrations (posttreatment days 55 and 95) were as follows: >1000 ng/g in thyroid, nails, liver, gall bladder and spleen; >200 and <1000 ng/g in lymph nodes, kidneys, adrenals, bones, skeletal muscles, heart and skin; and <200 ng/g in various brain structures, thymus, stomach, colon, pancreas. and teeth. Results from this study are therefore consistent with view that Sb(V) is reduced to Sb(III), the active form, within cells from where it is slowly eliminated. Localization of Sb active forms in the thyroid gland and liver and the pathophysiological consequences of marked Sb accumulation in these tissues warrant further studies.

Meglumine Antimoniate (Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB/c Mice Infected by Leishmania (Leishmania) infantum

“…Another hypothesis suggests that Sb V acts as a prodrug that is transformed into the more toxic trivalent form (Sb III ) to exert its antileishmanial activity (6)(7)(8)(9). In fact, some studies indicate that Sb III production in vivo is responsible for both therapeutic activity and antimony toxicity (10)(11)(12). Furthermore, we have confirmed this hypothesis by showing that meglumine antimoniate causes DNA damage in vivo but not in vitro.…”

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

“…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.…”

“…The therapeutic and toxic effects are apparently related to the residual levels of Sb, and the magnitude of these effects depends on both the Sb V drug daily dose and the length of the treatment course. During the slow elimination phase, Sb is found predominantly inside the red blood cells, with very little found in the plasma [8,9]. Many authors believe that some of the Sb V forms that penetrate erythrocytes and other cells are reduced intracellularly to Sb III , an antimony form that appears to be retained within the cell by forming complexes with organic molecules, such as glutathione (GSH) [1].…”

Antimony and Nickel

“…The slow terminal elimination phase was hypothesized to be due to conversion of Sb(V) to Sb(III). In rhesus monkeys, the terminal elimination phase half-life during a 21-day course of meglumine antimoniate therapy was found to be 35.8 days [28]. Posttreatment, antimony is localized within the liver, thyroid, and nails.…”