The Biological Fate of 14C-Dimercaptosuccinic Acid in Monkeys and Rabbits

Abstract

The biological fate of 14C-labeled dimercaptosuccinic acid (DMSA) in monkeys and rabbits was determined by measuring the 14C activity in their urine, feces, and expired air (14CO2). Monkeys absorbed less than 20% DMSA from three oral dose levels (0.082, 0.16, and 0.5 mmol/kg) of 14C-DMSA, and the rabbits absorbed 32% DMSA or less from an oral dose of 14C-DMSA (0.5 mmol/kg). Although the bioavailability of DMSA was limited in either species, DMSA was detected in the blood of both species within minutes after oral dosing. In either species, most of the radiolabel from the absorbed 14C-DMSA was detected in the urine within 12 hours. We also developed a sensitive assay for directly measuring levels of DMSA (as free thiols) in blood. Intact DMSA was not detected in the blood of the monkeys or the rabbits more than 200 minutes after oral or intravenous dosing at 0.5 mmol DMSA/kg body weight. However, 14C activity in blood and urine of the monkeys was measurable 72 hours after this dose. Differences between measured 14C concentrations and intact DMSA concentrations in the blood suggest the presence of DMSA metabolites that have longer half-lives than DMSA. Consequently, until the biological activities of these compounds are identified, the pharmacokinetic analysis of DMSA may be incomplete.

Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning

“…40 Although DMSA is distributed predominantly in the extracellular space because of its hydrophilic nature, 41 there is evidence in nonhuman primates that its volume of distribution is greater than the plasma volume, with values of 0.35 and 0.40 L/kg, respectively, reported for unchanged DMSA and "parent compound plus metabolites." 36 This suggests DMSA is distributed extravascularly, and this is consistent with its plasma concentration-time decay curve that fits a two-compartment model. 36 Experimental studies have demonstrated DMSA accumulation in renal proximal tubular cells through active (energy-requiring) organic anion transport at the basolateral membrane (the membrane at the tubular cell-peritubular capillary interface); 38,[42][43][44] this is now known to be a Na + -dependent dicarboxylate transporter.…”

“…36 This suggests DMSA is distributed extravascularly, and this is consistent with its plasma concentration-time decay curve that fits a two-compartment model. 36 Experimental studies have demonstrated DMSA accumulation in renal proximal tubular cells through active (energy-requiring) organic anion transport at the basolateral membrane (the membrane at the tubular cell-peritubular capillary interface); 38,[42][43][44] this is now known to be a Na + -dependent dicarboxylate transporter. 45 Uptake of nonprotein-bound DMSA from the vascular compartment in this manner promotes dissociation of plasma protein-bound drug.…”

“…35 Total urine retrieval was approximately 20% of the administered dose when DMSA was ingested, compared with approximately 81% when DMSA was administered intravenously. 36 However, retrieval of DMSA in urine following oral administration may not reflect total absorption, because fecal elimination, including nonabsorbed and biliary, was not measured 35 and enterohepatic circulation of DMSA and possibly also its metabolites is thought to occur. 37 38 In clinical studies most DMSA in plasma is protein (mainly albumin)-bound through a disulfide bond with cysteine; only a very small amount is present as free drug.…”

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans

“…In monkeys (Macaca mulatta) of 3-4 years old, with a weight of 2.7-3.7 kg, Tillotson et al [26] observed bi-phasic kinetics of 14 C-radiolabelled DMSA (i.e., parent and metabolites) and mono-phasic kinetics of unaltered DMSA. Therefore, we also considered a second alternative of our model, a 3-compartment model with two systemic compartments and a gut compartment with continuous bile flow.…”

Treatment of lead and arsenic poisoning in anuric patients – a case report and narrative review of the literature

“…DMSA has a low molecular weight of 182 Da, and a low volume of distribution of approximately 0.4 L/kg [18]. The molecular weights of DMSA-Pb and DMSA-Ars complex are 389 Da and 257 Da, respectively, based on the 1:1 DMSA-metal complex ratio.…”