Mechanistic Modeling of Monocarboxylate Transporter-Mediated Toxicokinetic/Toxicodynamic Interactions Between γ-Hydroxybutyrate and l -Lactate

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 K m for renal reabsorption of GHB (650 μg/mL) was close to its K m for the proton-dependent MCT1 and that for l -lactate (13.5 μg/mL) close to its K m for the sodium-dependent SMCT1. Inhibition of reabsorption by both agents was necessary to model concomitant drug administration. The metabolic K m 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 K m value of 1,865 μg/mL for brain uptake which is similar to the in vitro K m 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.