Metabolism of AM404 From Acetaminophen at Human Therapeutic Dosages in the Rat Brain.
BACKGROUND
Acetaminophen, an analgesic and antipyretic drug, has been used clinically for more than a century. Previous studies showed that acetaminophen undergoes metabolic transformations to form an analgesic compound, N-(4-hydroxyphenyl) arachidonamide (AM404), in the rodent brain. However, these studies were performed with higher concentrations of acetaminophen than are used in humans.


OBJECTIVE
The aim of the present study was to examine the metabolism of AM404 from acetaminophen in the rat brain at a concentration of 20 mg/kg, which is used in therapeutic practice in humans, and to compare the pharmacokinetics between them.


METHODS
We used rat brains to investigate the metabolism of AM404 from acetaminophen at concentrations (20 mg/kg) used in humans. In addition, we determined the mean pharmacokinetic parameters for acetaminophen and its metabolites, including AM404.


RESULTS
The maximum plasma concentrations of acetaminophen and AM404 in the rat brain were 15.8 µg/g and 150 pg/g, respectively, with corresponding AUC0-2h values of 8.96 μg hour/g and 117 pg hour/g. The tmax for both acetaminophen and AM404 was 0.25 hour.


CONCLUSIONS
These data suggest that AM404's concentration-time profile in the brain is similar to those of acetaminophen and its other metabolites. Measurement of blood acetaminophen concentration seems to reflect the concentration of the prospective bioactive substance, AM404.
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
Shun
S
Muramatsu
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
Seiji
S
Shiraishi
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
Kanako
K
Miyano
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan; Division of Molecular Pathology and Metabolic Disease, Department of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan.
Yuka
Y
Sudo
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Wakayama, Japan.
Akiko
A
Toda
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Wakayama, Japan.
Masayuki
M
Mogi
Division of Research and Development, Showa Yakuhin Kako Co., Ltd., Kawasaki, Japan.
Mayumi
M
Hara
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan; Division of Molecular Pathology and Metabolic Disease, Department of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan.
Akinobu
A
Yokoyama
Division of Research and Development, Showa Yakuhin Kako Co., Ltd., Kawasaki, Japan.
Yoshihiko
Y
Kawasaki
Division of Research and Development, Showa Yakuhin Kako Co., Ltd., Kawasaki, Japan.
Mikio
M
Taniguchi
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan; Division of Supportive Care Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan; Innovation Center for Supportive, Palliative and Psychosocial Care, National Cancer Center, Tokyo, Japan.
Yasuhito
Y
Uezono
Acetaminophen; Brain; N-(4-Hydroxyphenyl) Arachidonamide (AM404); Pharmacokinetics