Effect of chronic γ-hydroxybutyrate (GHB) administration on GHB toxicokinetics and GHB-induced respiratory depression

Abstract

Background. γ-hydroxybutyrate (GHB) has a high potential for illicit use; overdose of this compound results in sedation, respiratory depression and death. Tolerance to the hypnotic/sedative and electroencephalogram effects of GHB occurs with chronic GHB administration; however, tolerance to respiratory depression has not been evaluated. GHB toxicodynamic effects are mediated predominantly by GABAB receptors. Chronic treatment may affect monocarboxylate transporters (MCTs) and alter the absorption, renal clearance and brain uptake of GHB. Objectives. To determine effects of chronic GHB dosing on GHB toxicokinetics, GHB-induced respiratory depression, and MCT expression. Methods. Rats were administered GHB 600 mg/kg intravenously daily for 5 days. Plasma, urine and tissue samples and respiratory measurements were obtained on days 1 and 5. Plasma and urine were analyzed for GHB by LC/MS/MS and tissue samples for expression of MCT1, 2 and 4 and their accessory proteins by QRT-PCR. Results. No differences in GHB pharmacokinetics or respiratory depression were observed between days 1 and 5. Opposing changes in MCT 1 and MCT4 mRNA expression were observed in kidney samples on day 5 compared to GHB-naïve animals and MCT4 expression was increased in the intestine. Conclusions. The lack of tolerance observed with GHB-induced respiratory depression, in contrast to the tolerance reported for the sedative/hypnotic and electroencephalogram effects, suggests different GABAB receptor subtypes may be involved in different GABAB-mediated toxicodynamic effects of GHB. Chronic or binge users of GHB may be at no less risk for fatality from respiratory arrest with a GHB overdose than with a single dose of GHB.

Single‐ and Multiple‐Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies

“…However, the analgesic effect of baclofen at the doses necessary to reduce pain is accompanied by rapid development of tolerance and by side effects such as sedation, drowsiness, dizziness, and motor impairment, which limit its clinical use . Sodium oxybate (SXB), a GABA endogenous metabolite and GABA B agonist, has also shown benefits for the treatment of fibromyalgia; however, SXB has high abuse potential and serious side effects, including respiratory depression …”

“…6,10 Sodium oxybate (SXB), a GABA endogenous metabolite and GABA B agonist, has also shown benefits for the treatment of fibromyalgia 11 ; however, SXB has high abuse potential and serious side effects, including respiratory depression. 12 Positive allosteric modulators (PAMs) are molecules that potentiate receptor activation, initiated by the endogenous neurotransmitter or other agonists, by interacting with an allosteric binding site that is different from the agonist orthosteric binding site. PAMs do not have any intrinsic activity and are able to enhance activity only when the receptor is bound to the agonist.…”