Potential gamma-hydroxybutyric acid (GHB) drug interactions through blood-brain barrier transport inhibition: a pharmacokinetic simulation-based evaluation.
Recreational abuse or overdose of gamma-hydroxybutyric acid (GHB) results in dose-dependent central nervous system (CNS) effects including death. As GHB undergoes monocarboxylic acid transporter (MCT)-mediated transport across the blood-brain barrier (BBB), one possible strategy for the management of GHB toxicity/overdose involves inhibition of GHB BBB transport. To test this strategy, interactions between GHB and MCT substrates (salicylic acid or probenecid) were simulated. Competitive, noncompetitive and uncompetitive inhibition mechanisms were incorporated into the GHB-MCT substrate interaction model for inhibitor dosing either pre-, concurrent or post-GHB administration. Simulations suggested that salicylic acid was the better candidate to limit GHB accumulation in the CNS. A time window of effect (> 10% change) was observed for salicylic acid pre- and post-administration, with maximal transport inhibition occurring within 12 hr of pre- and 2 hr of post-administration. Consistent with the prediction that reduced GHB brain concentrations could translate to decreased pharmacodynamic effects, a pilot study in rats showed that the pronounced GHB sedative/hypnotic effects (24.0 +/- 6.51 min; n = 4) in the control group (1.58 mmol/kg GHB plus saline) were significantly (p < 0.05) abrogated by salicylic acid (1.25 mmol/kg) coadministration.
Bhattacharya
Indranil
I
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, H517 Cooke-Hochstetter, Buffalo, NY, USA. boje@buffalo.edu
Boje
Kathleen M K
KM
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010865:Pilot Projects; D011339:Probenecid / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D015203:Reproducibility of Results; D020156:Salicylic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics
D002352:Carrier Proteins; D006885:Hydroxybutyrates; C111420:4-hydroxybutyric acid; D020156:Salicylic Acid; D011339:Probenecid