Gamma-Butyrolactone Overdose Potentially Complicated by Co-Ingestion of Industrial Solvent N-Methyl-2-Pyrrolidone

Gamma-hydroxybutyrate (GHB) is misused as an intoxicant, either alone or concurrently with other substances. Because GHB is illegal, the precursor chemicals 1,4-butanediol and gamma-butyrolactone are also misused for the same effect, either through pre-ingestion alteration or endogenous metabolism to GHB. We describe a case of a 50-year-old man with a history of polysubstance misuse who experienced an overdose of GHB from gamma-butyrolactone ingestion. The patient also co-ingested a common industrial solvent, N-methyl-2-pyrrolidone (NMP). This co-ingested substance raised theoretical concern of metabolism to a GHB congener, underscoring that the emergence of new psychoactive substance use patterns requires ongoing vigilance and toxicologic confirmation.

Metabolism and Effects on Endogenous Metabolism of Paracetamol (Acetaminophen) in a Porcine Model of Liver Failure

The metabolic fate, toxicity, and effects on endogenous metabolism of paracetamol (acetaminophen, APAP) in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF). Anesthetized pigs were initially dosed at 250 mg/kg via an oroduodenal tube with APAP serum concentrations maintained above 300 mg/l using maintenance doses of 0.5–4 g/h until ALF. Studies were undertaken to determine both the metabolic fate of APAP and its effects on the endogenous metabolic phenotype of ALF in using 1H NMR spectroscopy. Increased concentrations of citrate combined with pre-ALF increases in circulating lactate, pyruvate, and alanine in plasma suggest mitochondrial dysfunction and a switch in hepatic energy metabolism to glycolysis in response to APAP treatment. A specific liquid chromatography-tandem mass spectrometry assay was used to quantify APAP and metabolites. The major circulating and urinary metabolite of APAP was the phenolic glucuronide (APAP-G), followed by p-aminophenol glucuronide (PAP-G) formed from N-deacetylated APAP. The PAP produced by N-deacetylation was the likely cause of the methemoglobinemia and kidney toxicity observed in this, and previous, studies in the pig. The phenolic sulfate of APAP, and the glutathione-derived metabolites of the drug were only found as minor components (with the cysteinyl conjugate detected but not the mercapturate). Given its low sulfation, combined with significant capacity for N-deacetylation the pig may represent a poor translational model for toxicology studies for compounds undergoing significant metabolism by sulfation, or which contain amide bonds which when hydrolyzed to unmask an aniline lead to toxicity. However, the pig may provide a useful model where extensive amide hydrolysis is seen for drugs or environmental chemicals in humans, but not in, eg, the rat and dog which are the preclinical species normally employed for safety assessment.

Metabolomics biotechnology, applications, and future trends: a systematic review

Given the highly increased incidence of human diseases, a better understanding of the related mechanisms regarding endogenous metabolism is urgently needed.