Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

Abstract

Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of g-hydroxybutyrate (GHB) and its precursor g-butyrolactone (GBL). GHB is a substrate for monocarboxylate transporters (MCTs), and increasing GHB renal clearance or decreasing GHB absorption via MCT inhibition represents a potential treatment strategy for GHB/GBL overdose. In these studies, GHB and GBL were administered in doses of 1.92, 5.77, and 14.4 mmol/kg orally with and without MCT inhibition to determine effects of this treatment strategy on the oral toxicokinetics and toxicodynamics of GHB and GBL. The competitive MCT inhibitor L-lactate was administered by intravenous infusion starting 1 hour after GHB and GBL administration. Oral administration of L-lactate and the MCT inhibitor luteolin was also evaluated. Respiratory depression was measured using plethysmography. Intravenous L-lactate, but not oral treatments, significantly increased GHB renal and/or oral clearances. At the low dose of GHB and GBL, i.v. L-lactate increased GHB renal clearance. Due to the increased contribution of renal clearance to total clearance at the moderate dose, increased renal clearance translated to an increase in oral clearance. At the highest GHB dose, oral clearance was increased without a significant change in renal clearance. The lack of effect of i.v. L-lactate on renal clearance after a high oral GHB dose suggests possible effects of i.v. L-lactate on MCT-mediated absorption. The resulting increases in oral clearance improved respiratory depression. Intravenous L-lactate also reduced mortality with the high GBL dose. These data indicate i.v. L-lactate represents a potential treatment strategy in oral overdose of GHB and GBL.

Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of γ-hydroxybutyric acid and l-lactate in rats

“…Our future modeling efforts will focus on translating this kidney model to humans in order to evaluate potential treatment strategies in GHB overdose. The following information will need be incorporated to achieve the translational potential of the proposed model: (1) since GHB is abused orally, a mechanistic PK model of GHB with non-linear absorption and first-pass elimination components will be needed [83,85], (2) scale-up of physiologically-relevant flow and volume parameters from rats to humans, and (3) estimation of all relevant V MAX parameters, while fixing the respective K M values to the observed in vitro data.…”

“…Similar to GHB, L-lactate is also a substrate for renal proton-coupled monocarboxylate transporters MCT 1, 2, and 4 (SLC16A family) and sodium-dependent monocarboxylate transporter 1 (SMCT1, SLC5A8) [78,79]. We have also demonstrated the inhibition of active renal reabsorption of GHB by inhibitors of MCT1, L-lactate and AR-C155858, as potential treatment strategies in GHB overdose in rats [80–83] and in humans [84]. We previously published a semi-mechanistic pharmacokinetic model for GHB that included a kidney component with three compartments, namely a site for GHB reabsorption and two transit compartments to characterize the delayed appearance of GHB in urine [81,85].…”

Effect of chronic γ-hydroxybutyrate (GHB) administration on GHB toxicokinetics and GHB-induced respiratory depression

“…Due to the role of MCTs in GHB renal reabsorption, increasing GHB renal clearance and inhibiting brain uptake via administration of MCT inhibitors represents a potential treatment strategy for GHB intoxication (13, 19, 35). Recent studies demonstrate the ability of MCT inhibitor administration to increase GHB oral clearance and decrease GHB brain:plasma partitioning as well, further supporting the potential of this therapeutic strategy (16, 20). If changes in MCT transporter expression may occur in chronic GHB users, the efficacy of this treatment strategy in this population may differ from that in acute overdose.…”

“…The toxicokinetics of GHB involve its transport by monocarboxylate transporters (MCTs), which govern many aspects of GHB toxicokinetics, including its oral absorption, renal reabsorption, and brain uptake (12–16). The first four members of the MCT family require a chaperone protein in order to be trafficked to the plasma membrane (17).…”

“…Both proteins contain a single transmembrane domain, share a conserved glutamate residue, have an intracellular C-terminus and a large glycosylated extracellular domain (18). Administration of MCT inhibitors in rats has been demonstrated to increase GHB renal and oral clearance and inhibit the brain uptake of GHB, making these inhibitors a potential treatment strategy for GHB overdose (13, 16, 19, 20). Prolonged exposure of MCT substrates, including lactate and butyrate, to cells which express MCT1 results in up-regulation of this transporter in vitro (21, 22).…”