Skip to main content
SpringerLink
Log in

γ-Hydroxybutyric Acid (GHB) Pharmacokinetics and Pharmacodynamics: Semi-Mechanistic and Physiologically Relevant PK/PD Model

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

An overdose of γ-hydroxybutyric acid (GHB), a drug of abuse, results in fatality caused by severe respiratory depression. In this study, a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize monocarboxylate transporter 1 (MCT1)-mediated transport of GHB, as well as effects of GHB on respiration frequency, for IV doses of 200, 600, and 1500 mg/kg in rats. The proposed PK/PD model for GHB consists of nonlinear metabolism of GHB in the liver, MCT1-mediated renal reabsorption with physiologically relevant concurrent fluid reabsorption, MCT1-mediated uptake into the brain, and direct effects of binding of GHB to GABAB receptors on the PD parameter, respiration frequency. Michaelis-Menten affinity constants for metabolism, renal reabsorption, and uptake into and efflux from the brain were fixed to the observed in vitro values. The IC 50 value for the effect of GHB on respiration frequency was fixed to a reported value for binding of GHB to GABAB receptors. All physiological parameters were fixed to the reported values for a 300-g rat. The model successfully captured the GHB PK/PD data and was further validated using the data for a 600-mg/kg dose of GHB after IV bolus administration. Unbound GHB brain ECF/blood partition coefficient (Kp u,u ) values obtained from the model agreed well with values calculated using experimental ECF concentrations obtained with brain microdialysis, demonstrating the physiological relevance of this model. Sensitivity analysis indicated that the PK/PD model was stable. In conclusion, we developed a semi-mechanistic and physiologically relevant PK/PD model of GHB using in vitro drug-transporter kinetics and in vivo PK/PD data in rats.

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
Fig. 5

Similar content being viewed by others

References

  1. Maitre M. The gamma-hydroxybutyrate signalling system in brain: organization and functional implications. Prog Neurobiol. 1997;51(3):337–61.

    Article  CAS  PubMed  Google Scholar 

  2. Mamelak M, Scharf MB, Woods M. Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings. Sleep. 1986;9(1 Pt 2):285–9.

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  4. Wong CG, Gibson KM, Snead OC 3rd. From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid. Trends Pharmacol Sci. 2004;25(1):29–34.

    Article  CAS  PubMed  Google Scholar 

  5. Schwartz RH, Milteer R, LeBeau MA. Drug-facilitated sexual assault ('date rape'). South Med J. 2000;93(6):558–61.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE. Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med. 2011;29(3):319–32.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Scharf MB, Lai AA, Branigan B, Stover R, Berkowitz DB. Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients. Sleep. 1998;21(5):507–14.

    Article  CAS  PubMed  Google Scholar 

  13. Arena C, Fung HL. Absorption of sodium gamma-hydroxybutyrate and its prodrug gamma-butyrolactone: relationship between in vitro transport and in vivo absorption. J Pharm Sci. 1980;69(3):356–8.

    Article  CAS  PubMed  Google Scholar 

  14. 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  CAS  PubMed  Google Scholar 

  15. Sporer KA, Chin RL, Dyer JE, Lamb R. Gamma-hydroxybutyrate serum levels and clinical syndrome after severe overdose. Ann Emerg Med. 2003;42(1):3–8.

    Article  PubMed  Google Scholar 

  16. Cui D, Morris ME. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Wang Q, Lu Y, Morris ME. Monocarboxylate transporter (MCT) mediates the transport of gamma-hydroxybutyrate in human kidney HK-2 cells. Pharm Res. 2007;24(6):1067–78.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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. 2007;35(8):1393–9.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Roiko SA, Felmlee MA, Morris ME. Brain uptake of the drug of abuse gamma-hydroxybutyric acid in rats. Drug Metab Dispos. 2012;40(1):212–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dave RA, Morris ME. Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of gamma-hydroxybutyric acid and L-lactate in rats. J Pharmacokinet Pharmacodyn. 2015;42(5):497–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Meno-Tetang GM, Li H, Mis S, Pyszczynski N, Heining P, Lowe P, et al. Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after oral and intravenous doses. Drug Metab Dispos. 2006;34(9):1480–7.

    Article  CAS  PubMed  Google Scholar 

  25. Peters SA. Appendices. Physiologically-based pharmacokinetic (PBPK) modeling and simulations: principles, methods, and applications in the pharmaceutical industry. Wiley; 2012. p. 407.

  26. Morse BL, Vijay N, Morris ME. Mechanistic modeling of monocarboxylate transporter-mediated toxicokinetic/toxicodynamic interactions between gamma-hydroxybutyrate and L-lactate. AAPS J. 2014;16(4):756–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Niederalt C, Wendl T, Kuepfer L, Claassen K, Loosen R, Willmann S, et al. Development of a physiologically based computational kidney model to describe the renal excretion of hydrophilic agents in rats. Front Physiol. 2012;3:494.

    PubMed  Google Scholar 

  28. Jobin J, Bonjour JP. Measurement of glomerular filtration rate in conscious unrestrained rats with inulin infused by implanted osmotic pumps. Am J Phys. 1985;248(5 Pt 2):F734–8.

    CAS  Google Scholar 

  29. Khurana I. Excretory system. Textbook of human physiology for dental students, second edition: Elsevier Health Sciences APAC; 2014. p. 280–1.

  30. Lash LH. Principles and methods of renal toxicology. In: Hayes AW, editor. Principles and methods of toxicology. Fifth Edition: Taylor & Francis; 2007. p. 1513–4.

    Google Scholar 

  31. Lote CJ. Summary of the principal reabsorptive and secretory processes. Principles of renal physiology, fourth edition. New York: Springer Science & Business Media; 2000. p. 161–2.

    Google Scholar 

  32. Wang X, Wang Q, Morris ME. Pharmacokinetic interaction between the flavonoid luteolin and gamma-hydroxybutyrate in rats: potential involvement of monocarboxylate transporters. AAPS J. 2008;10(1):47–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ishige K, Aizawa M, Ito Y, Fukuda H. Gamma-butyrolactone-induced absence-like seizures increase nuclear CRE- and AP-1 DNA-binding activities in mouse brain. Neuropharmacology. 1996;35(1):45–55.

    Article  CAS  PubMed  Google Scholar 

  35. Morse BL, Morris ME. Effects of monocarboxylate transporter inhibition on the oral toxicokinetics/toxicodynamics of gamma-hydroxybutyrate and gamma-butyrolactone. J Pharmacol Exp Ther. 2013;345(1):102–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vijay N, Morse BL, Morris ME. A novel monocarboxylate transporter inhibitor as a potential treatment strategy for gamma-hydroxybutyric acid overdose. Pharm Res. 2015;32(6):1894–906.

    Article  CAS  PubMed  Google Scholar 

  37. Vijay N, Morris ME. Role of monocarboxylate transporters in drug delivery to the brain. Curr Pharm Des. 2014;20(10):1487–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Woodhall PB, Tisher CC. Response of the distal tubule and cortical collecting duct to vasopressin in the rat. J Clin Invest. 1973;52(12):3095–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. D’Argenio DZ, Schumitzky A. and Wang X. ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software, fourth edition. Biomedical Simulations Resource, Los Angeles, CA 2009.

  42. Lyon RC, Johnston SM, Panopoulos A, Alzeer S, McGarvie G, Ellis EM. Enzymes involved in the metabolism of gamma-hydroxybutyrate in SH-SY5Y cells: identification of an iron-dependent alcohol dehydrogenase ADHFe1. Chem Biol Interact. 2009;178(1–3):283–7.

    Article  CAS  PubMed  Google Scholar 

  43. Zhang Y, Huo M, Zhou J, Xie S. PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Prog Biomed. 2010;99(3):306–14.

    Article  Google Scholar 

  44. Raybon JJ, Boje KM. Pharmacokinetics and pharmacodynamics of gamma-hydroxybutyric acid during tolerance in rats: effects on extracellular dopamine. J Pharmacol Exp Ther. 2007;320(3):1252–60.

    Article  CAS  PubMed  Google Scholar 

  45. Felmlee MA, Krzyzanski W, Morse BL, Morris ME. Use of a local sensitivity analysis to inform study design based on a mechanistic toxicokinetic model for gamma-hydroxybutyric acid. AAPS J. 2011;13(2):240–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

ACKNOWLEDGEMENTS

This work was supported by the National Institutes of Health National Institute on Drug Abuse [grant R01DA023223]. We would like to acknowledge Dr. Bridget Morse, Dr. Nisha Vijay, and Robert Jones for their contributions.

Author information

Author notes

  1. Rutwij A. Dave

    Present address: Preclinical and Translational Pharmacokinetics and Pharmacodynamics (PTPK), Genentech Inc., South San Francisco, California, USA

Authors and Affiliations

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

    Rutwij A. Dave, Kristin E. Follman & Marilyn E. Morris

Authors
  1. Rutwij A. Dave
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristin E. Follman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marilyn E. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marilyn E. Morris.

Electronic Supplementary Material

ESM 1

(DOCX 3207 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dave, R.A., Follman, K.E. & Morris, M.E. γ-Hydroxybutyric Acid (GHB) Pharmacokinetics and Pharmacodynamics: Semi-Mechanistic and Physiologically Relevant PK/PD Model. AAPS J 19, 1449–1460 (2017). https://doi.org/10.1208/s12248-017-0111-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-017-0111-7

KEY WORDS

Search

Navigation