Paracetamol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

No information

Author:

McEvoy, G.K. (ed.).

Year:

2007

Bibliographic source:

American Society of Health-System Pharmacists, Bethesda, MD. 2007

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Paracetamol

EC Number:

203-157-5

EC Name:

Paracetamol

Cas Number:

103-90-2

Molecular formula:

C8H9NO2

IUPAC Name:

.

Radiolabelling:

no

Test animals

Species:

human

Sex:

male

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Details on exposure:

In healthy men, steady-state oral bioavailability of 1.3-g doses of extended-release tablets of acetaminophen administered every 8 hours for a total of 7 doses was equal to 1-g doses of conventional tablets of acetaminophen given every 6 hours for a total of 7 doses.

Duration and frequency of treatment / exposure:

Every 8 hours for a total of 7 doses

Doses / concentrations

Dose / conc.:

1.3 other: gm

No. of animals per sex per dose / concentration:

Details not available

Control animals:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Acetaminophen is rapidly and almost completely absorbed from the GI tract following oral administration. Food may delay slightly absorption of extended-release tablets of acetaminophen

Main ADME results 2

Type:

distribution

Results:

Acetaminophen is rapidly and uniformly distributed into most body tissues. About 25% of acetaminophen in blood is bound to plasma proteins Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentratio

Main ADME results 3

Type:

metabolism

Results:

About 80-85% of the acetaminophen in the body undergoes conjugation principally with glucuronic acid and to a lesser extent with sulfuric acid. Acetaminophen also is metabolized by microsomal enzyme systems in the liver.

Main ADME results 4

Type:

excretion

Results:

Acetaminophen is excreted in urine principally as acetaminophen glucuronide with small amounts of acetaminophen sulfate and mercaptate and unchanged drug. Approximately 85% of a dose of acetaminophen is excreted in urine as free & conjugated acetaminophen

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Acetaminophen is rapidly and almost completely absorbed from the GI tract following oral administration. Food may delay slightly absorption of extended-release tablets of acetaminophen. Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentrations are attained within 10-60 or 60-120 minutes, respectively. Following oral administration of a single 500-mg conventional tablet or a single 650-mg extended-release tablet, average plasma acetaminophen concentrations of 2.1 or 1.8 ug/mL, respectively, occur at 6 or 8 hours, respectively. In addition, dissolution of the extended-release tablets may depend slightly on the gastric or intestinal pH. Dissolution appears to be slightly faster in the alkaline pH of the intestines compared with the acidic pH of the stomach; however, this is of no clinical importance. Following administration of conventional preparations of acetaminophen, only small amounts of the drug are detectable in plasma after 8 hours. The extended-release tablets of acetaminophen release the drug for up to 8 hours, but in vitro data indicate that at least 95% of the dose is released within 5 hours.

Details on distribution in tissues:

Acetaminophen is rapidly and uniformly distributed into most body tissues. About 25% of acetaminophen in blood is bound to plasma proteins. Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentrations are attained within 10-60 or 60-120 minutes, respectively. Following oral administration of a single 500-mg conventional tablet or a single 650-mg extended-release tablet, average plasma acetaminophen concentrations of 2.1 or 1.8 ug/mL, respectively, occur at 6 or 8 hours, respectively

Details on excretion:

Acetaminophen is excreted in urine principally as acetaminophen glucuronide with small amounts of acetaminophen sulfate and mercaptate and unchanged drug. Approximately 85% of a dose of acetaminophen is excreted in urine as free and conjugated acetaminophen within 24 hours after ingestion. Administration of acetaminophen to patients with moderate to severe renal impairment may result in accumulation of acetaminophen conjugates.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

 acetaminophen glucuronide
 acetaminophen sulfate
 acetaminophen mercaptate

Any other information on results incl. tables

Details on metabolism : About 80-85% of the acetaminophen in the body undergoes conjugation principally with glucuronic acid and to a lesser extent with sulfuric acid. Acetaminophen also is metabolized by microsomal enzyme systems in the liver.

Data indicate that small quantities of acetaminophen are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis and that high doses of acetaminophen may deplete glutathione so that inactivation of this toxic metabolite is decreased. At high doses, the capacity of metabolic pathways for conjugation with glucuronic acid and sulfuric acid may be exceeded, resulting in increased metabolism of acetaminophen by alternative pathways. In addition, it also has been suggested that in fasting individuals conjugation of high doses of acetaminophen with glucuronic acid may be reduced, secondary to decreased hepatic carbohydrate reserves and microsomal oxidation may be increased, resulting in increased risk of hepatotoxicity.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
In healthy humans, paracetamol (synonym = acetaminophen) is expected to have low bio-accumulation potential since approximately 85% of a dose of acetaminophen is excreted in urine as free and conjugated acetaminophen within 24 hours after ingestion. However, administration of acetaminophen to patients with moderate to severe renal impairment may result in accumulation of acetaminophen conjugates.
Thus, the bio-accumulation potential of paracetamol is expected to be related to the health status and age of the humans that are administered oral doses of the chemical

Executive summary:

In healthy humans, paracetamol (synonym = acetaminophen) is expected to have low bio-accumulation potential since approximately 85% of a dose of acetaminophen is excreted in urine as free and conjugated acetaminophen within 24 hours after ingestion. However, administration of acetaminophen to patients with moderate to severe renal impairment may result in accumulation of acetaminophen conjugates. Thus, the bio-accumulation potential of paracetamol is expected to be related to the health status and age of the humans that are administered oral doses of the chemical