Toxicokinetics/Toxicodynamics of γ-hydroxybutyrate-ethanol Intoxication: Evaluation of Potential Treatment Strategies

γ-Hydroxybutyrate (GHB), a common drug of abuse, is often coingested with ethanol. Increasing renal clearance via monocarboxylate transporter (MCT) inhibition represents a potential therapeutic strategy in GHB overdose, as does inhibition of GABAB receptors. In this study, we investigate toxicokinetic/toxicodynamic interactions between GHB-ethanol and efficacy of treatment options for GHB-ethanol intoxication in rats. Sedation was assessed using the endpoint of return-to-righting … Continued

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics of γ-hydroxybutyrate and γ-butyrolactone

Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of γ-hydroxybutyrate (GHB) and its precursor γ-butyrolactone (GBL). GHB is a substrate for monocarboxylate transporters (MCTs), and increasing GHB renal clearance or decreasing GHB absorption via MCT inhibition represents a potential treatment strategy for GHB/GBL overdose. In these studies, GHB and GBL … Continued

Phenanthrene Metabolism in Smokers: Use of a Two-step Diagnostic Plot Approach to Identify Subjects with Extensive Metabolic Activation

Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are among the most likely causes of lung cancer. PAHs require metabolic activation to initiate the carcinogenic process. Phenanthrene (Phe), a noncarcinogenic PAH, was used as a surrogate of benzo[α]pyrene and related PAHs to study the metabolic activation of PAHs in smokers. A dose of 10 μg of deuterated Phe([D10]Phe) was administered … Continued

Metabolism of [D10]Phenanthrene to Tetraols in Smokers for Potential Lung Cancer Susceptibility Assessment: Comparison of Oral and Inhalation Routes of Administration

Polycyclic aromatic hydrocarbons (PAHs) are believed to be among the causative agents for lung cancer in smokers. PAHs require metabolic activation for carcinogenicity. One pathway produces diol epoxides that react with DNA, causing mutations. Because diol epoxides are converted to tetraols, quantitation of tetraols can potentially be used to identify smokers who may be at … Continued

Three-dimensional Quantitative Structure-activity Relationship Studies on UGT1A9-mediated 3-O-glucuronidation of Natural Flavonols Using a Pharmacophore-based Comparative Molecular Field Analysis Model

Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., Km), Vmax, intrinsic clearance (CLint) = Vmax/Km] derived for flavonols. This article aims to construct position (3-OH)-specific … Continued

The Role of the Breast Cancer Resistance Protein (ABCG2) in the Distribution of Sorafenib to the Brain

ATP-binding cassette transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been shown to work in concert to restrict brain penetration of several tyrosine kinase inhibitors. It has been reported that P-gp is dominant in limiting transport of many dual P-gp/BCRP substrates across the blood-brain barrier (BBB). This study investigated the influence of P-gp … Continued

Concentration–Effect Relationships for the Drug of Abuse—γ-hydroxybutyric Acid

γ-Hydroxybutyric acid (GHB) is an endogenous neurotransmitter that is abused because of its sedative/hypnotic and euphoric effects. The objectives of this study were to evaluate the concentration-effect relationships of GHB in plasma, cerebrospinal fluid (CSF), brain (whole and discrete brain regions), and brain frontal cortex extracellular fluid. This information is crucial for future studies to … Continued

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