γ-hydroxybutyric acid: Toxicokinetics and toxicodynamics
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γ-hydroxybutyric acid (GHB) is an endogenous monocarboxylate formed from γ-aminobutyric acid. GHB is also administered as a therapeutic agent (sodium oxybate; Xyrem) and is consumed illicitly as a drug of abuse. An increased incidence of GHB toxicity and overdose has resulted from the illicit use of GHB. Current therapeutic strategies for the treatment of GHB overdose are limited to supportive care to treat the symptoms of GHB overdose which include respiratory depression, sedation, and coma. Potential therapeutic strategies based on the toxicokinetics and toxicodynamics of GHB have been proposed. Our laboratory has been investigating a toxicokinetics-based therapeutic strategy involving the inhibition of monocarboxylate transporter (MCT)-mediated active renal reabsorption of GHB. To better optimize this proposed therapeutic strategy the mechanisms underlying GHB toxicokinetics and toxicodynamics were investigated in this dissertation. The sedative/hypnotic effects of GHB are postulated to occur through direct or indirect interactions of GHB with the GABA B receptor. GHB sedative/hypnotic effect increased significantly with dose and plasma, brain (whole and discrete brain regions) and brain extracellular fluid concentrations correlated with the offset of sedative/hypnotic effect. In contrast, GABA and glutamate concentrations in discrete brain regions demonstrated no relationship with offset of sedative/hypnotic effect. Our results suggest that the sedative/hypnotic effects of GHB are mediated directly by GHB and that at supratherapeutic doses the formation of GABA from GHB may not contribute to the observed sedative/hypnotic effects. GHB demonstrates complex toxicokinetics with saturable renal clearance and capacity-limited metabolism. A semi-physiological mechanistic model describing saturable renal clearance and capacity-limited metabolism with simultaneous fitting of GHB plasma concentrations and urinary excretion data was developed in Chapter 3. The K m estimate for active renal reabsorption (0.46 mg/ml) was similar to in vitro assessments of affinities for MCT-mediated GHB uptake. Simulation studies demonstrated that inhibition of active renal reabsorption resulted in increased time-averaged renal clearance and decreased plasma AUC. Administration of a known MCT inhibitor, L-lactate, demonstrated similar changes in renal clearance and plasma AUC as observed in the simulation study. These results suggest that MCT-mediated inhibition of the active renal reabsorption of GHB represents a viable therapeutic strategy for the treatment of overdose cases. A local sensitivity analysis of the mechanistic toxicokinetic model for GHB was performed in Chapter 4 to further validate the developed model and to inform the design of future toxicokinetic studies with respect to dose selection and sampling. Model outputs (plasma concentration and urinary excretion) were sensitive to perturbations of all estimated parameters with the exception of distributional clearance parameters. Based on the results of the sensitivity analysis the 1000 mg/kg dose of GHB will be removed from all future studies as it is not required for parameter estimation. In addition, this analysis provided information regarding the segments of the plasma concentration time profile that are crucial for parameter estimation which allows for the design of sampling schemes to maximize sample collection during these regions. The proposed therapeutic strategy for the treatment of GHB overdose involves inhibition of MCTs in the kidney; however, MCT expression is observed in many tissues and therefore, may affect the distribution of GHB. GHB partition coefficients (K p ) varied in a dose- and tissue-dependent manner with nonlinear partitioning observed in the liver, kidney, lung, spleen, heart and frontal cortex. K p values increased with increasing dose in all tissues except the lung which demonstrates decreasing K p values. Co-administration of L-lactate (an MCT inhibitor) resulted in increased partitioning in the lung, spleen and kidney. These tissue distribution patterns are consistent with involvement of active uptake and efflux transporters and may be explained by MCT-mediated bidirectional transport. A number of mechanistic pharmacokinetic models describing active renal reabsorption have been reported in the literature. We investigated the performance of these models over a range of affinity (K m ) and capacity (V max ) parameter estimates and doses. Our results demonstrated that the plasma and urine compartments must be separated by at least a single compartment (representing the renal tubules) when active renal reabsorption is extensive. Further subdivision of the renal tubule compartment into proximal and distal tubule compartments introduced a delay in the appearance of drug in the urine; however, incorporation of these compartments into the model would be dependent on the urine sampling schedule that was utilized. The semi-physiological model (Model 4) may be used with compartmental or physiological distribution models thereby representing the most universally applicable model evaluated. In summary, this dissertation evaluated the mechanisms underlying the toxicokinetics and toxicodynamics of GHB in support of the use of a toxicokinetics-based therapeutic strategy for the treatment of GHB overdose. The research contained in this dissertation provides the framework required for the development of therapeutic strategies based on inhibition of MCT-mediated active renal reabsorption of GHB.