Abstract
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.
Highlights
Overdose of the analgesic drug paracetamol is a well-known cause of drug-induced liver injury (DILI)
The metabolic fate, toxicity, and effects on endogenous metabolism of paracetamol in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF)
Histopathological, and Biochemical Characterization of the ALF Model Following the administration of APAP, ALF was recorded at a median time of 17.5 6 2.7 h with a median total administered dose of 48.5 g (31.5–68.5 g)
Summary
Overdose of the analgesic drug paracetamol (acetaminophen, 4hydroxyacetanalide, APAP) is a well-known cause of drug-induced liver injury (DILI). As such APAP is a leading cause of acute liver failure (ALF), which is associated with high mortality and orthotopic liver transplantation (Lee, 2012). Previous studies with the model showed that chronic APAP dosing for up to 20 h led to ALF onset (Lee et al, 2013). During the course of this work on the evaluation of efficacy of the UCL-LDD we have taken the opportunity to attempt to better define both the metabolic fate of paracetamol and its effects on the endogenous metabolic phenotype in this porcine model of hepatotoxicity
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