Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans

Figures & data

Figure 1. Scheme of the two-compartment model. D_p.o. is the oral dose given. G is the gut. A is the rest of the body; k_f is the rate of removal of DMSA from the gut into the faeces; k_a is the rate of absorption from the gut into the rest of the body; k_b is the rate of removal of DMSA from the body into the gut; k_u is the rate of removal of DMSA from the body into urine. Note that k_s = k_b + k_u and k_g = k_a + k_f are parameters to be fitted.

Table 1. Characteristics of the healthy volunteers used for model calibration and model verification.

	Study	N	Age	% Men	Dose and route
Calibration	Asiedu et al. [16]	3	29 years (SD =10)	unknown	10 mg/kg p.o.
Verification	Aposhian et al. [17]	6	22–31 years	100	10 mg/kg p.o.
	Dart et al. [13]	5	22–31 years	100	10 mg/kg p.o.
	Maiorino et al. [10]	5	22–35 years	100	10 mg/kg p.o.

Table 2. Computer fitted model parameters (geometric mean and 95% confidence interval).

Model	ks^a (h^−1)	kg^b (h^−1)	RVd ^c (l/kg)
DMSA	0.19 (0.09;0.40)	1.69 (0.34;8.40)	0.25 (0.07;0.88)

DMSA: dimercaptosuccinic acid (succimer).

^a k_s is the total elimination rate of DMSA from the system (sum of excretion through bile and urine).

^b k_g is the total elimination rate of applied dose from the gut (sum of excretion to faeces and absorbed into the system).

^c R_Vd is the relative volume of distribution.

Figure 2. Model simulations of the individual experimental data from the Asiedu’s study [16] (N = 3 subjects: 1, 2 and 3). The measured total DMSA concentrations in plasma are represented by symbols and the predicted ones by a continuous line.

Figure 3. Simulated versus observed plasma concentrations and urine excretion of DMSA following oral administration of 10 mg/kg bodyweight in healthy human volunteers. Observed data are presented as mean ±95% CI.

Table 3. Comparison of the predicted values with the experimental data for DMSA plasma and urine concentrations (ratios of AUC and ratios of C_max values).

Metric	DMSA in plasma	DMSA in urine
AUC ratio
DMSA model AUC/Dart data AUC^a	0.9	NA
DMSA model AUC/Maiorino data AUC	0.9	0.7
DMSA model AUC/Aposhian data AUC	NA	0.8
Cmax ratio
DMSA model Cmax /Dart data Cmax^b	0.9	NA
DMSA model Cmax /Maiorino data Cmax	1.0	0.5

DMSA: dimercaptosuccinic acid (succimer); AUC: Area under the curve.

^a Ratio of: AUC predicted (median) curve/AUC of observed Dart (mean) curve after conversion of the blood concentrations into plasma concentrations.

^b Ratio of: C_max predicted (median) curve/ C_max observed in Dart (mean) curve after conversion of the blood concentrations into plasma concentrations.

Asiedu P, Moulton T, Blum CB, et al. Metabolism of meso-2,3-dimercaptosuccinic acid in lead-poisoned children and normal adults. Environ Health Perspect. 1995;103:734–739.

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