Drug‐drug interaction between diclofenac and gamma‐hydroxybutyric acid

• Published in: Biopharmaceutics & drug disposition 2021-09, Vol.42 (8), p.351-358
• Main Authors: Rodriguez‐Cruz, Vivian, Ren, Tianjing, Morris, Marilyn E.
• Format: Article
• Language: English
• Subjects: Anesthetics - pharmacokinetics; Anesthetics - toxicity; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Biological Transport, Active - drug effects; Brain - drug effects; Brain - metabolism; brain concentrations; Cataplexy; Cells, Cultured; DDI; Diclofenac; Diclofenac - pharmacokinetics; Dose-Response Relationship, Drug; Drug abuse; Drug dosages; Drug interaction; Drug Interactions; Endothelial cells; Endothelial Cells - metabolism; GHB; Hydroxybutyrates - pharmacokinetics; Hydroxybutyrates - toxicity; Inflammation; Monocarboxylic Acid Transporters - antagonists & inhibitors; Monocarboxylic Acid Transporters - metabolism; Narcolepsy; Nonsteroidal anti-inflammatory drugs; NSAID; Opioids; Pharmacodynamics; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Respiration; respiratory depression; Respiratory Insufficiency - chemically induced; Respiratory Insufficiency - drug therapy; Sleep and wakefulness; Sleep disorders; Sodium Oxybate - pharmacokinetics; Symporters - antagonists & inhibitors; Symporters - metabolism; Toxicity; γ-Hydroxybutyric acid
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.2296

Gamma hydroxybutyric acid (GHB) has been approved clinically to treat excessive daytime sleepiness and cataplexy in patients with narcolepsy, alcohol and opioid withdrawal, and as an anesthetic. The use of GHB clinically is limited due to its high abuse potential. The absorption, clearance and tissue uptake of GHB is mediated by proton‐dependent and sodium‐coupled monocarboxylate transporters (MCTs and SMCTs) and inhibition of these transporters may result in a change in GHB pharmacokinetics and pharmacodynamics. Previous studies have reported that non‐steroidal anti‐inflammatory drugs (NSAIDs) may inhibit these monocarboxylate transporters. Therefore, the purpose of this work was to analyze the interaction between GHB (at a dose of 600 mg/kg i. v.) and the NSAID, diclofenac, by examining the effects of this drug on the in vivo pharmacokinetics and pharmacodynamics in rat studies. The pharmacodynamic effect evaluated was respiratory depression, a measure of toxicity observed by GHB at this dose. There was an improvement in the respiratory rate with diclofenac administration suggesting an effect of diclofenac on GHB toxicity. In vitro studies with rat blood brain endothelial cells (RBE4) that express MCT1 indicated that diclofenac can inhibit GHB transport with an IC50 of 10.6 μM at pH 7.4. In vivo studies found a decrease in brain GHB concentrations and a decrease in the brain‐to‐plasma concentration ratio following diclofenac treatment. With this study we can conclude that diclofenac and potentially other NSAIDs can inhibit the transport of GHB into the brain, therefore decreasing GHB's pharmacodynamic effects and toxicity. This research provides in vitro and in vivo evidence that the NSAID diclofenac reverses the toxicity (as measured by respiratory depression) of the drug of abuse γ‐hydroxybutyric acid (GHB) by inhibiting the its Monocarboxylate Transporter 1‐mediated uptake into the brain. These findings are consistent with clinical studies suggesting a pharmacodynamic interaction of diclofenac in patients receiving the therapeutic GHB product Xyrem®.