Monoisoamyl 2, 3‐Dimercaptosuccinic Acid (MiADMSA) Demonstrates Higher Efficacy by Oral Route in Reversing Arsenic Toxicity: A Pharmacokinetic Approach

Abstract

Monoisoamyl DMSA (MiADMSA), a lipophilic chelating agent has emerged as a promising drug for the treatment of arsenic. The present study aimed at exploring the optimum dose and route of administration for achieving maximum arsenic elimination with minimal side effects. We also carried out a pharmacokinetic analysis of this drug to support arsenic chelation. Rats were exposed to arsenic (25 ppm) for 6 months and later received MiADMSA (50 or 100 mg ⁄ kg) orally and via i.p. route for 5 days. Oxidative stress parameters and arsenic levels in soft tissues, liver function test and histopathology of liver and kidney were performed. Plasma kinetic of MiADMSA (plasma-free drug and total drug) at 50 and 100 mg ⁄ kg p.o. was carried out. Arsenic exposure resulted in significant oxidative stress and hepatotoxicity. MiADMSA at 50 mg ⁄ kg dose administered orally provided about 45% and 75% protection against oxidative stress and in lowering body arsenic burden, respectively, against 25% and 40% via i.p. route. Pharmacokinetic analysis supported prolonged availability of the drug through oral administration. Collectively, these findings led us to conclude that oral administration of MiADMSA was more effective than intraperitoneal administration and that the minimum effective dose with least side effects was 50 mg ⁄ kg.Chelation therapy has been the basis for the medical therapy for metal poisoning. Chelating agent decreases metal toxicity by depleting the body burden of toxic metal by enhancing their excretion in addition to preventing these metals from binding to cellular targets [1]. The efficiency of chelating agent depends on multiple factors such as tissue distribution, time delay between metal intoxication and administration of the chelating agent, level of exposure and the dose ⁄ route administered. It has been known that DMSA can be used as an antidote for the treatment of arsenic toxicity; however, its efficacy against chronic arsenicosis is very limited [2]. Investigations have shown monoalkyl esters of DMSA to be far superior than DMSA, in mobilizing lead [3], cadmium [4,5] and mercury [6]. The efficiency increased with the number of carbon atoms in the alkyl group of DMSA monoester, and the best results were obtained with Monoisoamyl DMSA (MiADMSA). As treatment with DMSA is an accepted means for reducing the body burden of arsenic, the newer and more efficient monoesters, especially MiADMSA, deserve further attention [7]. MiADMSA is a water-soluble, lipophilic chelating agent. It is capable of chelating intracellular arsenic because of extensive cellular distribution. A large number of reports are available on the therapeutic efficacy of MiADMSA. Pande et al. [8] found that MiADMSA was effective in prevention and treatment of acute lead intoxication. Walker et al. [3] reported that MiADMSA reduced brain lead concentration by 75% when compared to 35% with DMSA.

Medical Countermeasures—Chelation Therapy

“…Further repeated administration of MiADMSA was found to be safe in adult rats followed by young and old rats, with female rats slightly more susceptible than males [98]. We also demonstrated that oral administration was more effective than the parental route [41,99,100]. Similarly to our studies, Kreppel et al [101] also reported the superior efficacy of MiADMSA and mono n-amyl DMSA in mice against lethal effects of arsenic.…”

“…Furthermore, pharmacokinetic analysis supported prolonged availability of the drug through oral administration [41]. These findings clearly suggest that oral administration of MiADMSA is more effective than intraperitoneal administration and that the minimum effective dose with the fewest side effects was 50 mg/kg [41]. Generation of free radicals in the case of arsenic toxicity is known to cause cellular apoptosis through a mitochondrial-driven pathway.…”

“…Our results indicated that orally administered MiADMSA reduced oxidative stress and arsenic burden by 45% and 75%, respectively, as compared to 25% and 40% through the intraperitoneal route. Furthermore, pharmacokinetic analysis supported prolonged availability of the drug through oral administration [41]. These findings clearly suggest that oral administration of MiADMSA is more effective than intraperitoneal administration and that the minimum effective dose with the fewest side effects was 50 mg/kg [41].…”

“…BAL therapy should continue until urinary arsenic levels are less than 50 μg/L per Oral administration of MiADMSA was more effective than intraperitoneal administration and the minimum effective dose with least side effects was 50 mg/kg Essential metal loss (copper and zinc) [41,42] 24 hours. Chelation is rarely needed outside the setting of symptomatic acute poisoning.…”

Arsenicals

“…Also, pharmacokinetic analysis supported prolonged availability of the drug through oral administration. Collectively, these findings led to the conclusion that oral administration of MiADMSA was more effective than intraperitoneal administration and that the minimum effective dose with the least side effects was 50 mg/kg (Flora et al, 2012). Generation of free radicals in case of arsenic toxicity is known to cause cellular apoptosis through a mitochondrial-driven pathway.…”