ANTIDOTAL EFFICACY OF NEWLY SYNTHESIZED DIMERCAPTOSUCCINIC ACID (DMSA) MONOESTERS IN EXPERIMENTAL ARSENIC POISONING IN MICE

The efficacy of four newly synthesized monoesters of meso-2,3-dimercap tosuccinic acid (DMSA), mono-i-amyl- (Mi-ADMS), mono-n-amyl- (Mn-ADMS) , mono-i-butyl- (Mi-BDMS), and mono-n-butyl-meso-2,3-dimercaptosuccina te (Mn-BDMS) in increasing survival and arsenic elimination in experim ental arsenic poisoning was investigated. Male mice (strain NMRI) rece ived arsenite sc (survival study: 130 mu mol/kg, 7 mice/group; elimina tion study: 85 mu mol/kg (LD5) together with a tracer dose of As-73(II I), 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 recei ved saline ip. In the survival study mice were observed for 30 days. I n the elimination study, the 73-arsenic content of several organs (blo od, liver, heart, lung, kidneys, spleen, testes, brain, small intestin e, large intestine, muscle, and skin) was measured 0.5, 2, 4, 6, and 8 hr after the arsenic injection using a gamma counter. Survival increa sed correspondingly well with the increase of arsenic elimination. DMS A, Mi-ADMS, Mn-ADMS, Mi-BDMS, and Mn-BDMS markedly decreased arsenic c ontent in most organs as soon as 1.5 hr after treatment. Only in small and large intestine were higher arsenic amounts found, indicating a s hift in arsenic elimination from the renal to the fecal route, and the reby suggesting a protective effect for the kidneys. Given ip, the mon oesters turned out to be similarly as effective as the parent drug DMS A. Following ig treatment, the DMSA monoesters Mi-ADMS and Mn-ADMS see med to be superior to DMSA with regard to survival. The similar effica cy of the various monoesters indicates that the side chain substitutio n did not markedly change bioavailability and efficacy. It is conclude d that the new DMSA monoesters are effective arsenic antidotes given s ystemically or orally. (C) 1995 Society of Toxicology.