The renal disposition of gamma-hydroxybutyric acid
The adverse effects of [gamma]-hydroxybutyric acid (GHB) overdose include coma, respiratory arrest and death; however, the only treatment is supportive care and there is no specific antidote or detoxification method. The objectives of this thesis are to characterize the renal clearance of GHB, study the transport mechanism of GHB in the mammalian kidney, and develop strategies to detoxify GHB after overdose by increasing GHB clearance. The renal clearance of GHB in rats increased as the dose increased, while the total and metabolic clearance decreased. The fraction of GHB reabsorbed decreased significantly as dose increased. Three strategies, using inhibitors for decreasing the active reabsorption of GHB, using osmotic diuretics for decreasing the passive reabsorption of GHB, and using a urinary alkalization agent for decreasing the passive reabsorption of GHB, significantly increased the renal and total clearances of GHB. Carrier-mediated transport of GHB was identified in brush-border and basolateral membrane vesicles prepared from rat kidney. The monocarboxylate transporter 1 (MCT1) was demonstrated to be a major transporter for GHB renal transport in rat kidney. Similarly, MCT1 was the major transporter for GHB transport in HK-2 cells (human kidney cells), while the contributions of MCT2 and MCT4 were minor. Flavonoids were demonstrated to be inhibitors for the MCT1-mediated transport of GHB, and luteolin significantly increased the renal and total clearances and decreased the toxicodynamic effect of GHB. A dose-dependent increase in the renal clearance and decrease in the toxicodynamic effect (sleep time) of GHB after L-lactate treatment was observed and a synergistic effect of D-mannitol and L-lactate treatment on the toxicodynamics of GHB were demonstrated in this thesis. A model consisting of both nonlinear metabolic and renal clearances was developed for GHB toxicokinetics with satisfactory prediction of the experimental data. A drug-drug interaction model was developed for the interaction at the renal transporter level and this model predicted that inhibition of GHB renal reabsorption significantly increases the total clearance of GHB when the concentration of the inhibitor was greater than its inhibition constant (K i ). In summary, the capacity-limited renal reabsorption of GHB was demonstrated. MCT1 is responsible, at least in part, for the renal transport of GHB and MCT inhibitors can be used for increasing GHB renal and total clearances. The combination of D-mannitol and L-lactate had a synergistic effect on the toxicodynamics of GHB and may represent a clinically feasible approach for the treatment of GHB overdose.