?-Hydroxybutyrate (GHB), a popular drug of abuse, is commonly ingested with alcohol at nightclubs and "raves", or as a means of drug-facilitated sexual assault. The range between high recreational doses and overdose is narrow, so that acute intoxications and overdoses are common. Respiratory depression and arrest represent the major cause of death in clinical reports of fatality associated with GHB intoxication. Effective pharmacological treatment for GHB overdoses has yet to be identified. The long-term objective is to identify treatment strategies that improve rates of morbidity and mortality associated with GHB intoxication, when GHB is ingested alone or with ethanol. We have reported that GHB undergoes concentration-dependent reabsorption in the kidney, due to transport by monocarboxylate transporters (MCTs), and that the administration of MCT inhibitors, such as L-lactate, can increase the renal and total clearances of GHB, decrease brain extracellular fluid concentrations of GHB, and decrease sleep time in rats. The purpose of this competing renewal is to determine the therapeutic potential of MCT inhibition as a treatment strategy for GHB overdose, alone and in combination with other potentially effective strategies, using the clinically relevant endpoint of respiratory depression.
Our specific aims are: (1) Characterization of GHB-induced respiratory depression and identification of treatment strategies that improve measures of respiration during GHB overdose. The purpose of this aim is to identify the mechanism of GHB-induced respiratory depression using selective neurotransmitter receptor antagonists. (2) Identification of effective treatment strategies for oral GHB overdoses. We hypothesize that MCTs are important for the absorption of GHB from the intestine, and that MCT inhibitors will decrease the bioavailability of GHB, as well as increasing its renal and total clearances following oral GHB intoxication. (3) Characterization of the GHB-alcohol interaction and identification of effective treatment strategies for oral GHB/alcohol overdoses. We hypothesize that high concentrations of ethanol will potentiate GHB-induced respiratory depression, and will increase the risk of fatality due to GHB intoxication. (4) Characterization of the toxicokinetics and toxicodynamics of GHB after multiple exposures and identification of effective treatment strategies. Our hypothesis is that binge use of GHB results in both increased expression of MCTs in tissues leading to altered transport and disposition, as well as tolerance to respiratory depression. Studies in this proposal will evaluate the use of oral and IV administered MCT inhibitors, alone or combined with neurotransmitter receptor antagonists, to improve measures of respiration and prevent fatality with GHB overdoses. This research is significant as it addresses the toxicodynamic effect, respiratory depression, mediating GHB fatality, and applies this endpoint under clinically relevant conditions. By combining treatment strategies with different mechanisms of action, this research will determine which pharmacological interventions have therapeutic potential to treat life-threatening GHB overdoses.

Public Health Relevance

?-Hydroxybutyrate (GHB), a popular drug of abuse, is commonly ingested with alcohol at nightclubs and "raves", or as a means of drug-facilitated sexual assault (date rape). GHB overdoses result in coma and death;there is currently no specific pharmacological treatment for GHB overdoses. The goal of this proposal is to identify specific therapeutic interventions for the treatment of GHB overdoses, when GHB is ingested alone or with alcohol, and apply these interventions under clinically relevant conditions of GHB abuse to determine their therapeutic potential for improving public health by preventing deaths due to GHB overdose.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA023223-05
Application #
8235448
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Frankenheim, Jerry
Project Start
2007-04-01
Project End
2017-06-30
Budget Start
2012-09-15
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$312,088
Indirect Cost
$99,588
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Vijay, Nisha; Morse, Bridget L; Morris, Marilyn E (2015) A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for ?-Hydroxybutyric Acid Overdose. Pharm Res 32:1894-906
An, Guohua; Wang, Xiaodong; Morris, Marilyn E (2014) Flavonoids are inhibitors of human organic anion transporter 1 (OAT1)-mediated transport. Drug Metab Dispos 42:1357-66
Vijay, Nisha; Morris, Marilyn E (2014) Role of monocarboxylate transporters in drug delivery to the brain. Curr Pharm Des 20:1487-98
Morse, Bridget L; Vijay, Nisha; Morris, Marilyn E (2014) Mechanistic modeling of monocarboxylate transporter-mediated toxicokinetic/toxicodynamic interactions between ?-hydroxybutyrate and L-lactate. AAPS J 16:756-70
Vijay, Nisha; Morris, Marilyn E (2014) Effect of 3,4-methylenedioxymethamphetamine on the toxicokinetics and sedative effects of the drug of abuse, ?-hydroxybutyric acid. J Pharm Sci 103:3310-5
Morris, Marilyn E; Dave, Rutwij A (2014) Pharmacokinetics and pharmacodynamics of phenethyl isothiocyanate: implications in breast cancer prevention. AAPS J 16:705-13
Roiko, Samuel A; Vijay, Nisha; Felmlee, Melanie A et al. (2013) Brain extracellular ýý-hydroxybutyrate concentrations are decreased by L-lactate in rats: role in the treatment of overdoses. Pharm Res 30:1338-48
Morse, Bridget L; Morris, Marilyn E (2013) Effects of monocarboxylate transporter inhibition on the oral toxicokinetics/toxicodynamics of ýý-hydroxybutyrate and ýý-butyrolactone. J Pharmacol Exp Ther 345:102-10
Morse, Bridget L; Morris, Marilyn E (2013) Toxicokinetics/Toxicodynamics of ýý-hydroxybutyrate-ethanol intoxication: evaluation of potential treatment strategies. J Pharmacol Exp Ther 346:504-13
Felmlee, Melanie A; Dave, Rutwij A; Morris, Marilyn E (2013) Mechanistic models describing active renal reabsorption and secretion: a simulation-based study. AAPS J 15:278-87

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