Mechanistic Modeling of Monocarboxylate Transporter-Mediated Toxicokinetic/Toxicodynamic Interactions Between γ-Hydroxybutyrate and l -Lactate
Journal Title: The AAPS Journal - Year 2014, Vol 16, Issue 4
Abstract
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.
Authors and Affiliations
Bridget L. Morse, Nisha Vijay, Marilyn E. Morris
Keywords
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- EP ID EP681703
- DOI 10.1208/s12248-014-9593-8
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