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

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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.

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Abbreviations

AUEC:

Area under the effect curve

AUC:

Area under the plasma concentration-time curve

Cl:

Clearance

ClM :

Metabolic clearance

ClR :

Renal clearance

Emax :

Maximum pharmacodynamic effect

GABA:

γ-aminobutyric acid

GHB:

γ-hydroxybutyrate

MCT:

Monocarboxylate transporter

Td :

Duration of effect

TK/TD:

Toxicokinetics/toxicodynamics

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Donna Ruszaj for her assistance in developing the current LC-MS/MS method. This work was supported by the National Institutes of Health National Institute on Drug Abuse [grant DA023223]. NV was funded in part by a fellowship from Pfizer Global Inc.

Authorship Contributions

Participated in research design: Morris, Vijay and Morse

Conducted experiments: Vijay and Morse

Contributed new reagents or analytic tools: Morris and Vijay

Performed data analysis: Vijay, Morris

Wrote or contributed to the writing of the manuscript: Morris and Vijay

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, New York, 14214-8033, USA

    Nisha Vijay, Bridget L. Morse & Marilyn E. Morris

  2. AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA

    Nisha Vijay

  3. Bristol-Myers Squibb, PO Box 4000, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA

    Bridget L. Morse

Authors
  1. Nisha Vijay
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  2. Bridget L. Morse
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  3. Marilyn E. Morris
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Correspondence to Marilyn E. Morris.

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Vijay, N., Morse, B.L. & Morris, M.E. A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose. Pharm Res 32, 1894–1906 (2015). https://doi.org/10.1007/s11095-014-1583-0

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  • DOI: https://doi.org/10.1007/s11095-014-1583-0

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