Plasma and hepatic concentrations of acetaminophen and its primary conjugates after oral administrations determined in experimental animals and humans and extrapolated by pharmacokinetic modeling

Plasma concentrations of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen were experimentally determined after oral administrations of 10 mg/kg in humanised-liver mice, control mice, rats, common marmosets, cynomolgus monkeys, and minipigs; the results were compared with reported human pharmacokinetic data. Among the animals tested, only rats predominantly converted acetaminophen to sulfate conjugates, rather than glucuronide conjugates. In contrast, the values of area under the plasma concentration curves of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen after oral administration of acetaminophen in marmosets and minipigs were consistent with those reported in humans under the present conditions. Physiologically based pharmacokinetic (PBPK) models (consisting of the gut, liver, and central compartments) for acetaminophen and its primary metabolite could reproduce and estimate, respectively, the plasma and hepatic concentrations of acetaminophen in experimental animals and humans after single virtual oral doses. The values of area under the curves of hepatic concentrations of acetaminophen estimated using PBPK models were correlated with the measured levels of cysteinyl acetaminophen (a deactivated metabolite) in plasma fractions in these species. Consequently, using simple PBPK models and plasma data to predict hepatic chemical concentrations after oral doses could be helpful as an indicator of in vivo possible hepatotoxicity of chemicals such as acetaminophen.

Automated summary

Experimental studies in various animals showed differences in the metabolism of acetaminophen, with only rats favoring sulfate conjugates over glucuronide conjugates. Marmosets and minipigs exhibited similar plasma concentration curves to humans after oral administration. Physiologically based pharmacokinetic models accurately estimated acetaminophen concentrations in experimental animals and humans, with the potential for predicting hepatotoxicity based on plasma data.