Monocarboxylate Transporter-Mediated Transport of γ-Hydroxybutyric Acid in Human Intestinal Caco-2 Cells

Lam, Wing Ki; Felmlee, Melanie A.; Morris, Marilyn E.

doi:10.1124/dmd.109.030775

Cited by 29 publications

(23 citation statements)

References 38 publications

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“…GHB and GBL are abused orally, and the oral absorption of high doses of GHB is dose-dependent in rats, with maximum plasma concentrations increasing less than proportionally with dose, indicating a saturable absorption process (Lettieri and Fung, 1979). Our in vitro studies in Caco-2 cells also indicate saturable transport of GHB, which is pH dependent and could be inhibited by MCT inhibitors (Lam et al, 2010). These studies suggest that, along with its concentration-dependent renal reabsorption, the dose-dependent oral absorption of GHB is also due to saturation of MCTs, which are present throughout the intestine in both rats and humans (Kirat et al, 2009;Merezhinskaya and Fishbein, 2009).…”

Section: Introductionmentioning

confidence: 72%

“…L-lactate on high oral doses of GHB. Additionally, although we have demonstrated GHB to be a substrate of MCT1, MCT2, and MCT4, and demonstrated pH-dependent transport of GHB in kidney and intestinal cells (Wang et al, 2006;Wang and Morris, 2007a;Lam et al, 2010), GHB and L-lactate are also substrates for the sodium-coupled SMCT1(SLC5A8) (Cui and Morris, 2009), which is also present in rat intestine and kidney (Ganapathy et al, 2008). Further experiments may also be warranted to distinguish the contribution of MCTs and SMCTs to GHB transport and the effects of L-lactate at both physiologic sites.…”

Section: Treatment Of Oral Ghb/gbl Overdosementioning

confidence: 99%

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

Morse

Morris

2013

J Pharmacol Exp Ther

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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.

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Section: Introductionmentioning

confidence: 72%

Section: Treatment Of Oral Ghb/gbl Overdosementioning

confidence: 99%

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

Morse

Morris

2013

J Pharmacol Exp Ther

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“…In rats, this dose-dependence has been demonstrated to be due to saturable metabolism, saturable oral absorption, and saturable renal reabsorption (Lettieri and Fung, 1979;Arena and Fung, 1980;Morris et al, 2005). Saturable oral absorption and renal reabsorption have been explained by the concentration-dependent transport of GHB by monocarboxylate transporters (MCTs) (Morris et al, 2005;Wang et al, 2006;Lam et al, 2010). MCTs are proton-coupled transporters with ubiquitous expression, including expression at the intestine, kidney, brain, and at the red blood cell (RBC) membrane.…”

Section: Introductionmentioning

confidence: 99%

γ-Hydroxybutyrate Blood/Plasma Partitioning: Effect of Physiologic pH on Transport by Monocarboxylate Transporters

Morse

Felmlee²,

Morris³

2011

Drug Metab Dispos

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ABSTRACT:The drug of abuse ␥-hydroxybutyrate (GHB) displays nonlinear renal clearance, which has been attributed to saturable renal reabsorption by monocarboxylate transporters (MCTs) present in the kidney. MCT1 is also present in red blood cells (RBCs); however, the significance of this transporter on the blood/plasma partitioning of GHB is unknown. The purpose of this research was to characterize the transport of GHB across the RBC membrane and assess GHB blood/plasma partitioning in vivo in the presence and absence of a competitive MCT inhibitor, L-lactate. In vitro experiments were performed using freshly isolated rat erythrocytes at pH values of 6.5 and 7.4. Inhibition with p-chloromercuribenzene sulfonate and 4,4-diisothiocyanostilbene-2,2-disulfonate were used to determine the contribution of MCT1 and band 3, respectively, on GHB uptake. For in vivo experiments, rats were administered GHB (400-1500 mg/kg) with and without L-lactate. In vitro experiments demonstrated that GHB is transported across the RBC membrane primarily by MCT1 at relevant in vivo concentrations. The K m for MCT1 was lower at pH 6.5 than that at pH 7.4, 2.2 versus 17.0 mM, respectively. The in vivo blood/plasma partitioning of GHB displayed linearity across all concentrations. L-Lactate coadministration increased GHB renal clearance but had no effect on the blood/ plasma ratio. Unlike its MCT-mediated transport in the intestine and kidneys, GHB blood/plasma partitioning appears to be linear and is unaffected by L-lactate. These findings can be attributed, at least in part, to differences in physiologic pH at different sites of MCT-mediated transport.

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“…In addition, it appears to be well tolerated in mice (no sign of sedation or abnormal behavior in the current studies). Robust synthetic routes to both HOCPCA and It has previously been reported that GHB is a substrate for MCT1, and the transporter is suggested to take part in the oral absorption and renal reabsorption of GHB, as well as GHB transport across the BBB (Bhattacharya and Boje, 2004;Wang et al, 2006;Lam et al, 2010). Given that GHB is a drug of abuse, for which no antidote is currently available, targeting MCT1-mediated transport holds great possibilities as a potential treatment strategy.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Evidence for Active Brain Uptake of the GHB Analog HOCPCA by the Monocarboxylate Transporter Subtype 1

Thiesen

Kehler

Clausen

et al. 2015

J Pharmacol Exp Ther

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g-Hydroxybutyric acid (GHB) is a recreational drug, a clinically prescribed drug in narcolepsy and alcohol dependence, and an endogenous substance that binds to both high-and lowaffinity sites in the brain. For studying the molecular mechanisms and the biologic role of the GHB high-affinity binding sites, ligands with high and specific affinity are essential. The conformationally restricted GHB analog HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid) is one such compound. The objective of this study was to investigate the transport of HOCPCA across the blood-brain barrier in vitro and in vivo and to investigate the hypothesis that HOCPCA, like GHB, is a substrate for the monocarboxylate transporters (MCTs). For in vitro uptake studies, MCT1, -2, and -4 were recombinantly expressed in Xenopus laevis oocytes, and the previously reported radioligand

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Monocarboxylate Transporter-Mediated Transport of γ-Hydroxybutyric Acid in Human Intestinal Caco-2 Cells

Abstract: ABSTRACT:The objectives of this study were to determine mRNA expression of monocarboxylate transporters (MCT) and to evaluate intestinal transport of the MCT substrates ␥-hydroxybutyrate (

Cited by 29 publications

References 38 publications

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

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

γ-Hydroxybutyrate Blood/Plasma Partitioning: Effect of Physiologic pH on Transport by Monocarboxylate Transporters

In Vitro and In Vivo Evidence for Active Brain Uptake of the GHB Analog HOCPCA by the Monocarboxylate Transporter Subtype 1

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