Mechanistic modeling of monocarboxylate transporter-mediated toxicokinetic/toxicodynamic interactions between...

Overdose of γ-hydroxybutyrate (GHB) can result in severe respiratory depression. Monocarboxylate transporter (MCT) inhibitors, including L-lactate, increase GHB clearance and represent a potential treatment for GHB intoxication. GHB can also affect L-lactate clearance, and L-lactate has been reported to affect respiration. In this research, we characterize these toxicokinetic/toxicodynamic interactions between GHB and L-lactate using mechanistic modeling. Plasma, urine, and respiration data were taken from our previous study in which GHB and sodium L-lactate were administered alone and concomitantly in rats. A model incorporating active renal reabsorption for both agents fit GHB and L-lactate toxicokinetic data. The Km for renal reabsorption of GHB (650 μg/mL) was close to its Km for the proton-dependent MCT1 and that for L-lactate (13.5 μg/mL) close to its Km for the sodium-dependent SMCT1. Inhibition of reabsorption by both agents was necessary to model concomitant drug administration. The metabolic Km for L-lactate closely resembled that for MCT-mediated hepatic uptake in vitro, and GHB inhibited this process. L-lactate significantly inhibited respiration at a high dose, and an indirect response model was used to fit these data. GHB toxicodynamics was modeled as a direct effect delayed by nonlinear transport into the brain extracellular fluid, with a Km value of 1,865 μg/mL for brain uptake which is similar to the in vitro Km value determined in rat brain endothelial cells. This model was useful for characterizing multiple MCT-mediated interactions. Incorporation of many parameters that can be determined in vitro may allow for clinical translation of these interactions.