| Autor: |
Toda A; Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Wakayama , Japan., Shimizu M; Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Tokyo , Japan., Uehara S; Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Tokyo , Japan.; Laboratory Animal Research Department, Central Institute for Experimental Animals , Kawasaki , Japan., Sasaki T; Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Tokyo , Japan., Miura T; Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Tokyo , Japan., Mogi M; Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Wakayama , Japan.; Drug Safety Research Laboratories, Shin Nippon Biomedical Laboratories, Ltd., Kagoshima , Japan., Utoh M; Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Wakayama , Japan.; Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Tokyo , Japan.; Scientific Affairs Division, Shin Nippon Biomedical Laboratories, Ltd., Tokyo , Japan., Suemizu H; Laboratory Animal Research Department, Central Institute for Experimental Animals , Kawasaki , Japan., Yamazaki H; Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Tokyo , Japan. |
| Abstrakt: |
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. |
