Skip to main content
SpringerLink
Log in

Brain Extracellular γ-hydroxybutyrate Concentrations are Decreased by L-lactate in Rats: Role in the Treatment of Overdoses

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

L-lactate represents a potential treatment for GHB overdose by inhibiting GHB renal reabsorption mediated by monocarboxylate transporters. Our objective was to assess the dose-dependence of L-lactate treatment, with and without D-mannitol, on GHB toxicokinetics/toxicodynamics (TK/TD).

Methods

Rats were administered GHB 600 mg/kg i.v. with L-lactate (low and high doses), D-mannitol, or L-lactate (low dose) with D-mannitol. GHB-induced sleep time and GHB plasma, urine and brain extracellular fluid (ECF) concentrations (by LC/MS/MS) were determined. The effect of L-lactate and D-mannitol on the uptake and efflux of GHB was assessed in rat brain endothelial RBE4 cells.

Results

L-lactate treatment increased GHB renal clearance from 1.4 ± 0.1 ml/min/kg (control) to 2.4 ± 0.2 and 4.7 ± 0.5 ml/min/kg after low and high doses, respectively, and reduced brain ECF AUC values to 65 and 25% of control. Sleep time was decreased from 137 ± 12 min (control) to 91 ± 16 and 55 ± 5 min (low and high L-lactate, respectively). D-mannitol did not alter GHB TK/TD and did not alter L-lactate’s effects on GHB TK/TD. L-lactate, but not D-mannitol, inhibited GHB uptake, and increased GHB efflux from RBE4 cells.

Conclusions

L-lactate decreases plasma and brain ECF concentrations of GHB, decreasing sedative/hypnotic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

aCSF:

artificial cerebrospinal fluid

AUC:

area under the plasma concentration-time curve

BBB:

blood–brain barrier

CHC:

α-cyano-4-hydroxycinnamate

Clr :

renal clearance

ECF:

extracellular fluid

GABA:

gamma-aminobutyric acid

GHB:

γ-hydroxybutyrate

MCT:

monocarboxylate transporter

TK/TD:

toxicokinetics/toxicodynamics

REFERENCES

  1. Andriamampandry C, Taleb O, Kemmel V, Humbert JP, Aunis D, Maitre M. Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain. FASEB J. 2007;21(3):885–95. Epub 2007/01/02.

    Article  PubMed  CAS  Google Scholar 

  2. Andriamampandry C, Taleb O, Viry S, Muller C, Humbert JP, Gobaille S, et al. Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB). FASEB J. 2003;17(12):1691–3.

    PubMed  CAS  Google Scholar 

  3. Gallimberti L, Spella MR, Soncini CA, Gessa GL. Gamma-hydroxybutyric acid in the treatment of alcohol and heroin dependence. Alcohol. 2000;20(3):257–62.

    Article  PubMed  CAS  Google Scholar 

  4. Dyer JE. Gamma-hydroxybutyrate: a health-food product producing coma and seizurelike activity. Am J Emerg Med. 1991;9(4):321–4.

    Article  PubMed  CAS  Google Scholar 

  5. Halkitis PN, Palamar JJ, Mukherjee PP. Poly-club-drug use among gay and bisexual men: a longitudinal analysis. Drug Alcohol Depend. 2007;89(2–3):153–60. Epub 2007/02/03.

    Article  PubMed  Google Scholar 

  6. Varela M, Nogue S, Oros M, Miro O. Gamma hydroxybutyrate use for sexual assault. Emerg Med J. 2004;21(2):255–6.

    Article  PubMed  CAS  Google Scholar 

  7. Okun MS, Boothby LA, Bartfield RB, Doering PL. GHB: an important pharmacologic and clinical update. J Pharm Pharm Sci. 2001;4(2):167–75.

    PubMed  CAS  Google Scholar 

  8. Wood DM, Nicolaou M, Dargan PI. Epidemiology of recreational drug toxicity in a nightclub environment. Subst Use Misuse. 2009;44(11):1495–502. Epub 2009/11/27.

    PubMed  Google Scholar 

  9. Mason PE, Kerns 2nd WP. Gamma hydroxybutyric acid (GHB) intoxication. Acad Emerg Med. 2002;9(7):730–9.

    Article  PubMed  Google Scholar 

  10. Wang Q, Lu Y, Yuan M, Darling IM, Repasky EA, Morris ME. Characterization of monocarboxylate transport in human kidney HK-2 cells. Mol Pharm. 2006;3(6):675–85. Epub 2006/12/05.

    Article  PubMed  CAS  Google Scholar 

  11. Wang Q, Morris ME. The role of monocarboxylate transporter 2 and 4 in the transport of gamma-hydroxybutyric acid in mammalian cells. Drug Metab Dispos Biol Fate Chem. 2007;35(8):1393–9. Epub 2007/05/16.

    Article  PubMed  CAS  Google Scholar 

  12. Fishbein WN, Merezhinskaya N, Foellmer JW. Relative distribution of three major lactate transporters in frozen human tissues and their localization in unfixed skeletal muscle. Muscle Nerve. 2002;26(1):101–12.

    Article  PubMed  CAS  Google Scholar 

  13. Leino RL, Gerhart DZ, Drewes LR. Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Brain Res Dev Brain Res. 1999;113(1–2):47–54.

    Article  PubMed  CAS  Google Scholar 

  14. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999;343(Pt 2):281–99.

    Article  PubMed  CAS  Google Scholar 

  15. Wang Q, Wang X, Morris ME. Effects of L-lactate and D-mannitol on gamma-hydroxybutyrate toxicokinetics and toxicodynamics in rats. Drug Metab Dispos Biol Fate Chem. 2008;36(11):2244–51. Epub 2008/08/23.

    Article  PubMed  CAS  Google Scholar 

  16. Carter LP, Koek W, France CP. Behavioral analyses of GHB: receptor mechanisms. Pharmacol Ther. 2009;121(1):100–14. Epub 2008/11/18.

    Article  PubMed  CAS  Google Scholar 

  17. Morse BL, Vijay N, Morris ME. Gamma-hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose. Mol Pharmacol. 2012;82(2):226–35. Epub 2012/05/09.

    Google Scholar 

  18. Roiko SA, Felmlee MA, Morris ME. Brain uptake of the drug of abuse gamma-hydroxybutyric acid in rats. Drug Metab Dispos Biol Fate Chem. 2012;40(1):212–8. Epub 2011/10/25.

    Article  PubMed  CAS  Google Scholar 

  19. Felmlee MA, Roiko SA, Morse BL, Morris ME. Concentration-effect relationships for the drug of abuse gamma-hydroxybutyric acid. J Pharmacol Exp Ther. 2010;333(3):764–71. Epub 2010/03/11.

    Article  PubMed  CAS  Google Scholar 

  20. Morris ME, 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.

    Article  PubMed  CAS  Google Scholar 

  21. Rapoport SI. Osmotic opening of the blood–brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol. 2000;20(2):217–30. Epub 2000/03/04.

    Article  PubMed  CAS  Google Scholar 

  22. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. New York: Academic; 1986.

    Google Scholar 

  23. de Lange EC, de Boer AG, Breimer DD. Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev. 2000;45(2–3):125–48. Epub 2000/12/08.

    Article  PubMed  Google Scholar 

  24. Bouw MR, Hammarlund-Udenaes M. Methodological aspects of the use of a calibrator in in vivo microdialysis-further development of the retrodialysis method. Pharm Res. 1998;15(11):1673–9. Epub 1998/12/02.

    Article  PubMed  CAS  Google Scholar 

  25. Felmlee MA, Wang Q, Cui D, Roiko SA, Morris ME. Mechanistic toxicokinetic model for gamma-hydroxybutyric acid: inhibition of active renal reabsorption as a potential therapeutic strategy. AAPS J. 2010;12(3):407–16. Epub 2010/05/13.

    Google Scholar 

  26. Ronaldson PT, Lee G, Dallas S, Bendayan R. Involvement of P-glycoprotein in the transport of saquinavir and indinavir in rat brain microvessel endothelial and microglia cell lines. Pharm Res. 2004;21(5):811–8. Epub 2004/06/08.

    Article  PubMed  CAS  Google Scholar 

  27. Smith JP, Drewes LR. Modulation of monocarboxylic acid transporter-1 kinetic function by the cAMP signaling pathway in rat brain endothelial cells. J Biol Chem. 2006;281(4):2053–60. Epub 2005/11/23.

    Article  PubMed  CAS  Google Scholar 

  28. Bhattacharya I, Boje KM. GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood–brain barrier. J Pharmacol Exp Ther. 2004;311(1):92–8.

    Article  PubMed  CAS  Google Scholar 

  29. Morse BL, Felmlee MA, Morris ME. Gamma-hydroxybutyrate blood/plasma partitioning: effect of physiologic pH on transport by monocarboxylate transporters. Drug Metab Dispos Biol Fate Chem. 2012;40(1):64–9. Epub 2011/10/07.

    Article  PubMed  CAS  Google Scholar 

  30. Wang Q, Darling IM, Morris ME. Transport of gamma-hydroxybutyrate in rat kidney membrane vesicles: role of monocarboxylate transporters. J Pharmacol Exp Ther. 2006;318(2):751–61. Epub 2006/05/19.

    Article  PubMed  CAS  Google Scholar 

  31. Roux F, Couraud PO. Rat brain endothelial cell lines for the study of blood–brain barrier permeability and transport functions. Cell Mol Neurobiol. 2005;25(1):41–58. Epub 2005/06/21.

    Article  PubMed  Google Scholar 

  32. Morris ME, Felmlee MA. Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse gamma-hydroxybutyric acid. AAPS J. 2008;10(2):311–21. Epub 2008/06/05.

    Article  PubMed  CAS  Google Scholar 

  33. Stanley WC, Wisneski JA, Gertz EW, Neese RA, Brooks GA. Glucose and lactate interrelations during moderate-intensity exercise in humans. Metabolism. 1988;37(9):850–8. Epub 1988/09/01.

    Article  PubMed  CAS  Google Scholar 

  34. Tappy L, Cayeux MC, Chiolero R. Effects of sodium lactate on ventilation and acid–base balance in healthy humans. Clin Physiol. 1996;16(4):393–401. Epub 1996/07/01.

    Article  PubMed  CAS  Google Scholar 

  35. Morris ME, Morse BL, Baciewicz GJ, Tessena MM, Acquisto NM, Hutchinson DJ, et al. Monocarboxylate transporter inhibition with osmotic diuresis increases gamma-hydroxybutyrate renal elimination in humans: a proof-of-concept study. J Clin Toxicol. 2011;1:105. doi:10.4172/2161-0494.1000105.

    CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the National Institutes of Health National Institute on Drug Abuse [grant DA023223]. NV was funded by a fellowship from Pfizer Global Inc.

Author information

Author notes

  1. Samuel A. Roiko

    Present address: Gilllette Children’s Speciality Healthcare, 183 University Ave. E., Saint Paul, MN, 55101, USA

Authors and Affiliations

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

    Samuel A. Roiko, Nisha Vijay, Melanie A. Felmlee & Marilyn E. Morris

  2. Department of Pharmaceutical Sciences, State University of New York, Buffalo, 352 Kapoor Hall, Buffalo, New York, 14214-8033, USA

    Marilyn E. Morris

Authors
  1. Samuel A. Roiko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nisha Vijay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melanie A. Felmlee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marilyn E. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marilyn E. Morris.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roiko, S.A., Vijay, N., Felmlee, M.A. et al. Brain Extracellular γ-hydroxybutyrate Concentrations are Decreased by L-lactate in Rats: Role in the Treatment of Overdoses. Pharm Res 30, 1338–1348 (2013). https://doi.org/10.1007/s11095-013-0973-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-0973-z

KEY WORDS

Search

Navigation