Drug-drug interaction between diclofenac and gamma-hydroxybutyric acid.

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.

Comparison of predicted and real propofol and remifentanil concentrations in plasma and brain tissue during target-controlled infusion: a prospective observational study.

Target-controlled infusion systems are increasingly used to administer intravenous anaesthetic drugs to achieve a user-specified plasma or effect-site target concentration. While several studies have investigated the ability of the underlying pharmacokinetic-dynamic models to predict plasma concentrations, there are no data on their performance in predicting drug concentrations in the human brain. We assessed the predictive performance of the Marsh propofol model and Minto remifentanil model for plasma and brain tissue concentrations. Plasma samples were obtained during neurosurgery from 38 patients, and brain tissue samples from nine patients. Propofol and remifentanil concentrations were measured using gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry. Data were analysed from the nine patients in whom both plasma and brain samples were simultaneously obtained. For the Minto model (five patients), the median performance error was 72% for plasma and -14% for brain tissue concentration predictions. The model tended to underestimate plasma remifentanil concentrations, and to overestimate brain tissue remifentanil concentrations. For the Marsh model (five patients), the median prediction errors for plasma and brain tissue concentrations were 12% and 81%, respectively. However, when the data from all blood propofol assays (36 patients) were analysed, the median prediction error was 11%, with overprediction in 15 (42%) patients and underprediction in 21 (58%). These findings confirm earlier reports demonstrating inaccuracy for commonly used pharmacokinetic-dynamic models for plasma concentrations and extend these findings to the prediction of effect-site concentrations.

Derivation of an occupational exposure level for manganese in welding fumes.

Exposure to high levels of manganese (Mn) in occupational settings is known to lead to adverse neurological effects. Since Mn is an essential nutrient, there are mechanisms that maintain its homeostatic control in the body, and there is some level of Mn in air that does not perturb Mn homeostasis. However, the Mn exposure concentrations at which no adverse effects are expected in occupational settings vary considerably across regulatory agencies. We set out to derive a Mn Occupational Exposure Level (OEL) for welders based on a review of studies that evaluated Mn exposure concentrations from welding fumes and: (1) neurological effects in welders; (2) levels of Mn in the brains of welders (via pallidal index [PI] estimated from magnetic resonance imaging [MRI]); (3) other biomarkers of Mn exposure in welders (i.e., blood and urine); and (4) Mn brain concentrations, PI, and corresponding neurological effects in non-human primates. Our analysis suggests uncertainty in quantifying dose-response associations for Mn from many of the occupational welding studies. The few welding studies that adequately estimate exposure suggest a possible OEL of 100-140µg/m3 for respirable Mn. This range is consistent with other epidemiology studies, studies of biomarkers of Mn exposure in welders, and with studies in non-human primates, though future studies could provide a stronger basis for deriving a Mn occupational guideline for welders.

The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats.

The distribution, clearance, and bioavailability of (2S,6S)-hydroxynorketamine has been studied in the Wistar rat. The plasma and brain tissue concentrations over time of (2S,6S)-hydroxynorketamine were determined after intravenous (20 mg/kg) and oral (20 mg/kg) administration of (2S,6S)-hydroxynorketamine (n = 3). After intravenous administration, the pharmacokinetic parameters were estimated using noncompartmental analysis and the half-life of drug elimination during the terminal phase (t 1/2) was 8.0 ± 4.0 h and the apparent volume of distribution (V d) was 7352 ± 736 mL/kg, clearance (Cl) was 704 ± 139 mL/h per kg, and the bioavailability was 46.3%. Significant concentrations of (2S,6S)-hydroxynorketamine were measured in brain tissues at 10 min after intravenous administration, ∼30 µg/mL per g tissue which decreased to 6 µg/mL per g tissue at 60 min. The plasma and brain concentrations of (2S,6S)-hydroxynorketamine were also determined after the intravenous administration of (S)-ketamine, where significant plasma and brain tissue concentrations of (2S,6S)-hydroxynorketamine were observed 10 min after administration. The (S)-ketamine metabolites (S)-norketamine, (S)-dehydronorketamine, (2S,6R)-hydroxynorketamine, (2S,5S)-hydroxynorketamine and (2S,4S)-hydroxynorketamine were also detected in both plasma and brain tissue. The enantioselectivity of the conversion of (S)-ketamine and (R)-ketamine to the respective (2,6)-hydroxynorketamine metabolites was also investigated over the first 60 min after intravenous administration. (S)-Ketamine produced significantly greater plasma and brain tissue concentrations of (2S,6S)-hydroxynorketamine relative to the (2R,6R)-hydroxynorketamine observed after the administration of (R)-ketamine. However, the relative brain tissue: plasma concentrations of the enantiomeric (2,6)-hydroxynorketamine metabolites were not significantly different indicating that the penetration of the metabolite is not enantioselective.

Considerations on manganese (Mn) treatments for in vitro studies.

Manganese (Mn) is an environmental risk factor for neuronal dysfunction and neurodegeneration of the basal ganglia and other brain regions. Aberrant brain Mn levels have been linked to manganism, Parkinson's disease (PD), Huntington's disease (HD) and other neurological disorders. Research on the cellular basis of Mn neurotoxicity has relied upon in vitro or non-human model systems. However, an analysis of relevant Mn concentrations for in vitro studies is lacking - and few studies have examined intracellular Mn levels. Here we perform calculations to evaluate in vitro exposure paradigms in relation to relevant in vivo levels of Mn post-exposure.