Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid: Inhibition of Active Renal Reabsorption as a Potential Therapeutic Strategy

Abstract

Abstract. γ-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacitylimited 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.

Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-Based Study

“…1) were selected for analysis based on the available models within the literature (16)(17)(18)(19). The differential equations for the structural models are listed in the supplemental data.…”

“…In our evaluation, we used four published mechanistic models with varying degrees of complexity describing active renal reabsorption (16,17) and active renal secretion (18,19). These mechanistic models include specific transport kinetic parameters that are driven by a physiologically relevant drug concentration (plasma/blood or tubular lumen) as opposed to evaluating renal clearance as a singular parameter.…”

“…Therefore, these models were excluded from the present analysis. In contrast to the compartmental models, the models developed for γ-hydroxybutyric acid and phenolsulfonphthalein (PSP) incorporate system-specific parameters, including renal blood flow, glomerular filtration rate (GFR), and urine flow which can be fixed (17). A mechanistic model for passive renal reabsorption has been described in the literature (22); however, it was not evaluated in the present study.…”

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

“…Reported models of active secretion and reabsorption have different structures and levels of complexity (14,(44)(45)(46). Both active secretion and reabsorption can be described using well-stirred or parallel tube models, relating the intrinsic secretion clearance to the renal blood flow (secretion), or the tubular filtrate flow (reabsorption) (11,22).…”

“…This can be achieved by either mathematically describing the simultaneous reabsorption of water and drug along the length of the tubule, or using a model with multiple compartments that each represents a region of the tubule with respective tubular flow rate value (14,23,(47)(48)(49)(50). The latter approach was applied in models of transporter mediated renal reabsorption of γ-hydroxybutyric acid in rat (36,44). The advantage of using a multiple compartment model of passive tubular reabsorption is that it can be readily extended to account for metabolism and transport processes in particular compartments.…”