A Novel Monocarboxylate Transporter Inhibitor As a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2014 Dec 7

PMID 25480120

Citations 18

Authors

Nisha Vijay

Bridget L Morse

Marilyn E Morris

Affiliations

Soon will be listed here.

Abstract

Purpose: Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for γ-hydroxybutyric acid (GHB) overdose by blocking its renal reabsorption in the kidney. This study further evaluated the effects of a novel, highly potent MCT inhibitor, AR-C155858, on GHB toxicokinetics/toxicodynamics (TK/TD).

Methods: Rats were administered GHB (200, 600 or 1500 mg/kg i.v. or 1500 mg/kg po) with and without AR-C155858. Breathing frequency was continuously monitored using whole-body plethysmography. Plasma and urine samples were collected up to 8 h. The effect of AR-C155858 on GHB brain/plasma partitioning was also assessed.

Results: AR-C155858 treatment significantly increased GHB renal and total clearance after intravenous GHB administration at all the GHB doses used in this study. GHB-induced respiratory depression was significantly improved by AR-C155858 as demonstrated by an improvement in the respiratory rate. AR-C155858 treatment also resulted in a significant reduction in brain/plasma partitioning of GHB (0.1 ± 0.03) when compared to GHB alone (0.25 ± 0.02). GHB CLR and CLoral (CL/F) following oral administration were also significantly increased following AR-C155858 treatment (from 1.82 ± 0.63 to 5.74 ± 0.86 and 6.52 ± 0.88 to 10.2 ± 0.75 ml/min/kg, respectively).

Conclusion: The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.

Citing Articles

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References

Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, Orlando R . Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol. 1993; 45(4):353-6. DOI: 10.1007/BF00265954. View

Morse B, Vijay N, Morris M . γ-Hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose. Mol Pharmacol. 2012; 82(2):226-35. PMC: 3400846. DOI: 10.1124/mol.112.078154. View

Ovens M, Davies A, Wilson M, Murray C, Halestrap A . AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10. Biochem J. 2009; 425(3):523-30. PMC: 2811425. DOI: 10.1042/BJ20091515. View

Morse B, Felmlee M, Morris M . γ-Hydroxybutyrate blood/plasma partitioning: effect of physiologic pH on transport by monocarboxylate transporters. Drug Metab Dispos. 2011; 40(1):64-9. PMC: 3250051. DOI: 10.1124/dmd.111.041285. View

Galicia M, Nogue S, Miro O . Liquid ecstasy intoxication: clinical features of 505 consecutive emergency department patients. Emerg Med J. 2011; 28(6):462-6. DOI: 10.1136/emj.2008.068403. View

Roiko S, Vijay N, Felmlee M, Morris M . Brain extracellular γ-hydroxybutyrate concentrations are decreased by L-lactate in rats: role in the treatment of overdoses. Pharm Res. 2013; 30(5):1338-48. PMC: 3618608. DOI: 10.1007/s11095-013-0973-z. View

Wang Q, Morris M . Flavonoids modulate monocarboxylate transporter-1-mediated transport of gamma-hydroxybutyrate in vitro and in vivo. Drug Metab Dispos. 2006; 35(2):201-8. DOI: 10.1124/dmd.106.012369. View

Halestrap A, Price N . The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999; 343 Pt 2:281-99. PMC: 1220552. View

Carai M, Colombo G, Brunetti G, Melis S, Serra S, Vacca G . Role of GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid. Eur J Pharmacol. 2001; 428(3):315-21. DOI: 10.1016/s0014-2999(01)01334-6. View

10.

Pahlman C, Qi Z, Murray C, Ferguson D, Bundick R, Donald D . Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1. Transpl Int. 2012; 26(1):22-9. DOI: 10.1111/j.1432-2277.2012.01579.x. View

11.

Gopal E, Fei Y, Sugawara M, Miyauchi S, Zhuang L, Martin P . Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate. J Biol Chem. 2004; 279(43):44522-32. DOI: 10.1074/jbc.M405365200. View

12.

Lettieri J, Fung H . Dose-dependent pharmacokinetics and hypnotic effects of sodium gamma-hydroxybutyrate in the rat. J Pharmacol Exp Ther. 1979; 208(1):7-11. View

13.

Lettieri J, Fung H . Absorption and first-pass metabolism of 14C-gamma-hydroxybutyric acid. Res Commun Chem Pathol Pharmacol. 1976; 13(3):425-37. View

14.

Felmlee M, Roiko S, Morse B, Morris M . Concentration-effect relationships for the drug of abuse gamma-hydroxybutyric acid. J Pharmacol Exp Ther. 2010; 333(3):764-71. PMC: 2879942. DOI: 10.1124/jpet.109.165381. View

15.

Cui D, Morris M . The drug of abuse gamma-hydroxybutyrate is a substrate for sodium-coupled monocarboxylate transporter (SMCT) 1 (SLC5A8): characterization of SMCT-mediated uptake and inhibition. Drug Metab Dispos. 2009; 37(7):1404-10. PMC: 2698941. DOI: 10.1124/dmd.109.027169. View

16.

Ganapathy V, Thangaraju M, Gopal E, Martin P, Itagaki S, Miyauchi S . Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008; 10(1):193-9. PMC: 2751467. DOI: 10.1208/s12248-008-9022-y. View

17.

Drasbek K, Christensen J, Jensen K . Gamma-hydroxybutyrate--a drug of abuse. Acta Neurol Scand. 2006; 114(3):145-56. DOI: 10.1111/j.1600-0404.2006.00712.x. View

18.

KAUFMAN E, Nelson T . An overview of gamma-hydroxybutyrate catabolism: the role of the cytosolic NADP(+)-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway. Neurochem Res. 1991; 16(9):965-74. DOI: 10.1007/BF00965839. View

19.

Morse B, Morris M . Effects of monocarboxylate transporter inhibition on the oral toxicokinetics/toxicodynamics of γ-hydroxybutyrate and γ-butyrolactone. J Pharmacol Exp Ther. 2013; 345(1):102-10. PMC: 3608444. DOI: 10.1124/jpet.112.202796. View

20.

Morris M, Hu K, Wang Q . Renal clearance of gamma-hydroxybutyric acid in rats: increasing renal elimination as a detoxification strategy. J Pharmacol Exp Ther. 2005; 313(3):1194-202. DOI: 10.1124/jpet.105.083253. View