y-Hydroxybutyrate (GHB) remains a popular drug of abuse, commonly known as liquid ecstasy;it is often ingested with alcohol, with other drugs of abuse, or as its precursors y-butyrolactone and 1, 4-butanediol. GHB intoxication results in CNS and respiratory depression and overdoses result in coma and death. A recent review stated that GHB was the second most common drug detected in urine of young people presenting with drug-induced coma, just behind cocaine. There is currently no specific 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 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 can increase the renal and total clearances of GHB. Results from our Preliminary Studies indicate that low doses of L-lactate combined with mannitol (an osmotic diuretic) increase GHB renal and total clearances, decrease serum concentrations, and decrease the return to righting reflex (RRR), a pharmacological end-point in rats, following high doses of GHB: the combined treatment resulted in an additive/synergistic effect on RRR. Our hypothesis is that administration of MCT inhibitors alone, or combined with mannitol, represents potential strategies for treating patients following overdoses of GHB.
Our specific aims are: (1) To determine the mechanism(s) underlying the effect of MCT inhibitors on GHB toxicokinetics (TK) and toxicodynamics (TD). We will test the hypothesis that MCT inhibitors alter the TK and TD of GHB by multiple mechanisms: increased renal clearance of GHB resulting in an increased total clearance;inhibition of GHB brain uptake;and decreased formation of GABA in the brain. 2) To determine the effects of mannitol on GHB TK and TD, and the mechanism(s) underlying the enhanced pharmacological effect of L-lactate produced by concomitant mannitol administration. (3) To determine the mechanisms for the effect of ethanol on the TK/TD of GHB, and the efficacy of MCT inhibitors and mannitol on GHB TK and TD following the concomitant administration of ethanol. (4) To perform a clinical study in normal volunteers to evaluate the efficacy of L-lactate/mannitol treatment in increasing the elimination and decreasing plasma concentrations of GHB. Methods used in the proposal include in vivo studies in rats to determine plasma, brain tissue and extracellular fluid (ECF) concentrations (by microdialysis) of GHB and the neurotransmitter y-aminobutyric acid (GABA). The concentration-effect (RRR) relationship for GHB will be determined. Effects on brain uptake will be determined using in situ brain perfusion, and in vitro studies of GHB brain metabolism will utilize mitochondrial and cytosolic tissue preparations. The clinical study will provide """"""""proof-of-concept"""""""" that the administration of L-lactate and mannitol can increase the elimination of GHB in humans, thereby representing a potential treatment for GHB overdoses.
|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|
|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|
|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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