Mechanistic toxicokinetic model for gamma-hydroxybutyric acid: inhibition of active renal reabsorption as a potential therapeutic strategy

Abstract

gamma-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacity-limited metabolism. The objectives of this study were to construct a mechanistic toxicokinetic (TK) model describing saturable renal reabsorption and capacity-limited metabolism of GHB and to predict the effects of inhibition of renal reabsorption on GHB TK in the plasma and urine. GHB was administered by iv bolus (200-1,000 mg/kg) to male Sprague-Dawley rats and plasma and urine samples were collected for up to 6 h post-dose. GHB concentrations were determined by LC/MS/MS. GHB plasma concentration and urinary excretion were well-described by a TK model incorporating plasma and kidney compartments, along with two tissue and two ultrafiltrate compartments. The estimate of the Michaelis-Menten constant for renal reabsorption (K (m,R)) was 0.46 mg/ml which is consistent with in vitro estimates of monocarboxylate transporter (MCT)-mediated uptake of GHB (0.48 mg/ml). Simulation studies assessing inhibition of renal reabsorption of GHB demonstrated increased time-averaged renal clearance and GHB plasma AUC, independent of the inhibition mechanism assessed. Co-administration of GHB (600 mg/kg iv) and L: -lactate (330 mg/kg iv bolus plus 121 mg/kg/h iv infusion), a known inhibitor of MCTs, resulted in a significant decrease in GHB plasma AUC and an increase in time-averaged renal clearance, consistent with the model simulations. These results suggest that inhibition of renal reabsorption of GHB is a viable therapeutic strategy for the treatment of GHB overdoses. Furthermore, the mechanistic TK model provides a useful in silico tool for the evaluation of potential therapeutic strategies.

Fig. 1

Final structural model for population toxicokinetic analysis. Refer to Table I for parameter descriptions

Fig. 2

VPC plots following iv administration of GHB for the final population model detailed in Fig. 1 and Table I. Solid squares represent individual data points (N = 7–10 rats per dose). The plotted lines are based on 1,000 simulated plasma concentration-time (panels a, c, e, and g) and urinary excretion (b, d, f, and h) profiles for each dose. The mean (solid line) and 10th (dotted line) and 90th (dashed line) percentiles were calculated from the predicted concentrations. GHB doses: a, b 200 mg/kg; c, d 400 mg/kg; e, f 600 mg/kg; g, h 1,000 mg/kg

Fig. 3

Simulations of GHB-transporter inhibitor interactions in rats. GHB was administered IV in the absence (solid line) or presence of a fixed concentration of inhibitor where R (I/K _i) is equal to 1 (dashed line), 10 (dotted line), and 100 (dot/dash line). Simulations of plasma concentration-time and urinary excretion profiles were conducted based on competitive inhibition of renal reabsorption. GHB doses: a, b 200 mg/kg; c, d 400 mg/kg; e, f 600 mg/kg; g, h 1,000 mg/kg