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Metabolism of AM404 From Acetaminophen at Human Therapeutic Dosages in the Rat Brain.

Muramatsu S, Shiraishi S, Miyano K, Sudo Y, Toda A, Mogi M, Hara M, Yokoyama A, Kawasaki Y, Taniguchi M, Uezono Y - Anesth Pain Med (2016)

Bottom Line: The tmax for both acetaminophen and AM404 was 0.25 hour.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT

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.

Objectives: 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.

Materials and 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.

No MeSH data available.


Related in: MedlinePlus

Plasma Concentration-Time Profile of Acetaminophen in Rats After Oral Administration at a Concentration of 20 mg/kgEach point represents the mean ± SD of data obtained from three rats.
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fig26359: Plasma Concentration-Time Profile of Acetaminophen in Rats After Oral Administration at a Concentration of 20 mg/kgEach point represents the mean ± SD of data obtained from three rats.

Mentions: In the present study, the mean plasma concentration-time profiles and pharmacokinetic parameters of acetaminophen in rats were calculated following oral administration of 20 mg/kg doses (Figure 1 and Table 1). The mean plasma concentration-time profiles and pharmacokinetic parameters for the two major metabolites of acetaminophen-acetaminophen sulfate (Sul) and acetaminophen glucuronide (Glu) are shown in Figure 2A and Table 1. Acetaminophen cysteine (Sys) and acetaminophen mercapturate acid (Mer), which were metabolized from N-acetyl-p-benzoquinone-imine (NAPQI) after conjugation with glutathione, are also shown in Figure 2B and Table 1. The plasma concentration curves of acetaminophen, Sul, Glu, Sys, and Mer indicated rapid, monophasic decline, with t1/2 values of 0.298, 0.361, 0.416, 0.483, and 0.779, respectively. The maximum plasma concentration (Cmax) and the peak time to reach Cmax (Tmax) of acetaminophen were 15.8 µg/g and 0.25 hour, respectively (Table 1). The Tmax value was the same for Sul and Glu (0.25 hour) and for Sys and Mer (0.5 hour). The value of the area under the plasma concentration-time curve (AUC0-2h) of acetaminophen was 8.96 μg hour/g. Figure 3 shows the mean brain concentration-time profiles and pharmacokinetic parameters of AM404 following oral administration of acetaminophen to rats at 20 mg/kg. The curve representing the brain concentrations of AM404 declined rapidly in a monophasic manner, with t1/2 of 0.305 hour (Table 2). The Cmax, Tmax, and AUC0-2h values of AM404 were 150 pg/g, 0.25 hour, and 117 pg hour/g, respectively (Table 2). Although efforts were made to measure the concentration of AM404 in plasma, these levels were undetectable under the experimental conditions applied (data not shown).


Metabolism of AM404 From Acetaminophen at Human Therapeutic Dosages in the Rat Brain.

Muramatsu S, Shiraishi S, Miyano K, Sudo Y, Toda A, Mogi M, Hara M, Yokoyama A, Kawasaki Y, Taniguchi M, Uezono Y - Anesth Pain Med (2016)

Plasma Concentration-Time Profile of Acetaminophen in Rats After Oral Administration at a Concentration of 20 mg/kgEach point represents the mean ± SD of data obtained from three rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834746&req=5

fig26359: Plasma Concentration-Time Profile of Acetaminophen in Rats After Oral Administration at a Concentration of 20 mg/kgEach point represents the mean ± SD of data obtained from three rats.
Mentions: In the present study, the mean plasma concentration-time profiles and pharmacokinetic parameters of acetaminophen in rats were calculated following oral administration of 20 mg/kg doses (Figure 1 and Table 1). The mean plasma concentration-time profiles and pharmacokinetic parameters for the two major metabolites of acetaminophen-acetaminophen sulfate (Sul) and acetaminophen glucuronide (Glu) are shown in Figure 2A and Table 1. Acetaminophen cysteine (Sys) and acetaminophen mercapturate acid (Mer), which were metabolized from N-acetyl-p-benzoquinone-imine (NAPQI) after conjugation with glutathione, are also shown in Figure 2B and Table 1. The plasma concentration curves of acetaminophen, Sul, Glu, Sys, and Mer indicated rapid, monophasic decline, with t1/2 values of 0.298, 0.361, 0.416, 0.483, and 0.779, respectively. The maximum plasma concentration (Cmax) and the peak time to reach Cmax (Tmax) of acetaminophen were 15.8 µg/g and 0.25 hour, respectively (Table 1). The Tmax value was the same for Sul and Glu (0.25 hour) and for Sys and Mer (0.5 hour). The value of the area under the plasma concentration-time curve (AUC0-2h) of acetaminophen was 8.96 μg hour/g. Figure 3 shows the mean brain concentration-time profiles and pharmacokinetic parameters of AM404 following oral administration of acetaminophen to rats at 20 mg/kg. The curve representing the brain concentrations of AM404 declined rapidly in a monophasic manner, with t1/2 of 0.305 hour (Table 2). The Cmax, Tmax, and AUC0-2h values of AM404 were 150 pg/g, 0.25 hour, and 117 pg hour/g, respectively (Table 2). Although efforts were made to measure the concentration of AM404 in plasma, these levels were undetectable under the experimental conditions applied (data not shown).

Bottom Line: The tmax for both acetaminophen and AM404 was 0.25 hour.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT

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.

Objectives: 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.

Materials and 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.

No MeSH data available.


Related in: MedlinePlus