Antidotal Efficacy of Newly Synthesized Dimercaptosuccinic Acid (DMSA) Monoesters in Experimental Arsenic Poisoning in Mice

Abstract

Antidotal Efficacy of Newly Synthesized Dimercaptosuccinic Acid (DMSA) Monoesters in Experimental Arsenic Poisoning in Mice. Kreppel, H., Reichl, F. X., Kleine, A., Szinicz, L., Singh, P. K., and Jones, M. M. (1995). Fundam. Appl. Toxicol. 26, 239-245. The efficacy of four newly synthesized monoesters of meso-2, 3-dimercaptosuccinic acid (DMSA), mono- i-amyl- (M i-ADMS), mono- n-amyl- (M n-ADMS), mono- i-butyl- (M i-BDMS), and mono- n-butyl- meso-2, 3-dimercaptosuccinate (M n-BDMS) in increasing survival and arsenic elimination in experimental arsenic poisoning was investigated. Male mice (strain NMRI) received arsenite sc (survival study: 130 μmol/kg, 7 mice/group; elimination study: 85 μmol/kg (LD5) together with a tracer dose of 73As(III), 6 mice/group). After 30 min mice were treated with 0.7 mmol/kg of DMSA or a monoester ip or via gastric tube (ig). Control animals received saline ip. In the survival study mice were observed for 30 days. In the elimination study, the 73-arsenic content of several organs (blood, liver, heart, lung, kidneys, spleen, testes, brain, small intestine, large intestine, muscle, and skin) was measured 0.5, 2, 4, 6, and 8 hr after the arsenic injection using a gamma counter. Survival increased correspondingly well with the increase of arsenic elimination. DMSA, M i-ADMS, M n-ADMS, M i-BDMS, and M n-BDMS markedly decreased arsenic content in most organs as soon as 1.5 hr after treatment. Only in small and large intestine were higher arsenic amounts found, indicating a shift in arsenic elimination from the renal to the fecal route, and thereby suggesting a protective effect for the kidneys. Given ip, the monoesters turned out to be similarly as effective as the parent drug DMSA. Following ig treatment, the DMSA monoesters M i-ADMS and M n-ADMS seemed to be superior to DMSA with regard to survival. The similar efficacy of the various monoesters indicates that the side chain substitution did not markedly change bioavailability and efficacy. It is concluded that the new DMSA monoesters are effective arsenic antidotes given systemically or orally.