?-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.
?-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.
|Guan, Xiaowen; Ruszaj, Donna; Morris, Marilyn E (2018) Development and validation of a liquid chromatography tandem mass spectrometry assay for AZD3965 in mouse plasma and tumor tissue: Application to pharmacokinetic and breast tumor xenograft studies. J Pharm Biomed Anal 155:270-275|
|Follman, Kristin E; Dave, Rutwij A; Morris, Marilyn E (2018) Effects of renal impairment on transporter-mediated renal reabsorption of drugs and renal drug-drug interactions: A simulation-based study. Biopharm Drug Dispos 39:218-231|
|Follman, Kristin E; Morris, Marilyn E (2018) Prediction of the Effects of Renal Impairment on Clearance for Organic Cation Drugs that Undergo Renal Secretion: A Simulation-Based Study. Drug Metab Dispos 46:758-769|
|Jones, Robert S; Parker, Mark D; Morris, Marilyn E (2017) Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6. Mol Pharm 14:2930-2936|
|Morris, Marilyn E; Rodriguez-Cruz, Vivian; Felmlee, Melanie A (2017) SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers. AAPS J 19:1317-1331|
|Dave, Rutwij A; Follman, Kristin E; Morris, Marilyn E (2017) ?-Hydroxybutyric Acid (GHB) Pharmacokinetics and Pharmacodynamics: Semi-Mechanistic and Physiologically Relevant PK/PD Model. AAPS J 19:1449-1460|
|Felmlee, Melanie A; Morse, Bridget L; Follman, Kristin E et al. (2017) The Drug of Abuse Gamma-Hydroxybutyric Acid Exhibits Tissue-Specific Nonlinear Distribution. AAPS J 20:21|
|Morse, Bridget L; Chadha, Gurkishan S; Felmlee, Melanie A et al. (2017) Effect of chronic ?-hydroxybutyrate (GHB) administration on GHB toxicokinetics and GHB-induced respiratory depression. Am J Drug Alcohol Abuse 43:686-693|
|Jones, R S; Morris, M E (2016) Monocarboxylate Transporters: Therapeutic Targets and Prognostic Factors in Disease. Clin Pharmacol Ther 100:454-463|
|Dave, Rutwij A; Morris, Marilyn E (2016) A quantitative threshold for high/low extent of urinary excretion of compounds in humans. Biopharm Drug Dispos 37:287-309|
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