3-[(4-aminobenzoyl)amino]propanoic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2000

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

A single oral dose of radiolabelled ABA was given to rats. Blood samples were collected at 15 min and 2 and 6 hours after dosing. Urine and faeces samples were collected from 0-6, 6-12 and 12-24 hrs after dosing. Plasma and urine levels of ABA and its metabolite NABA were determined using HPLC. The radioactivity was determined using liquiid scintillation counting.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

3-[(4-aminobenzoyl)amino]propanoic acid

EC Number:

616-017-7

Cas Number:

7377-08-4

Molecular formula:

C10 H12 N2 O3

IUPAC Name:

3-[(4-aminobenzoyl)amino]propanoic acid

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

not specified

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Dose / conc.:

64 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

Not specified

Control animals:

not specified

Details on dosing and sampling:

A single oral dose of 64 mg/kg was given. Blood samples were taken at 15 minutes, 2 and 6 hrs after dosing. Urine and faecal samples were collected from 0-6, 6-12 and 12-24 hrs after dosing.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

14% as calculated using the radioactivity found in the urine following oral and i.v. administrations (see seperate summary for iv)

Main ADME results 2

Type:

distribution

Results:

Maximum plasma levels of ABA, NABA and radioactivity were reached 15 minutes after dosing. Values were 0.0034, 0.0116 and 0.0163 micromol/ml respectively.

Main ADME results 3

Type:

metabolism

Results:

The ratio of the maximum plasma levels of ABA to NABA after only 15 minutes from dosing, was already 0.0034:0.0116, which indicates 77% metabolism of the dosed ABA to its N-acetylated metabolite NABA.

Main ADME results 4

Type:

excretion

Results:

Plasma radioactivity declined quickly and was below the limit of detection 24 hrs after dosing.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The 14% oral absorption stated in the review of the study is assumed to refer to bioavailability rather than GI tract absorption, which is different. Bioavailability in pharmacology (which is the context of the review) relates to a comparison of the amount of a substance in the plasma when administered via i.v. against the plasma concentration for the same dose but given orally. In this case, the comparison has used levels in urine instead of plasma, after 24 hrs. In this case therefore, 14% bioavailability would indicate a > 14% GI tract absorption, with the balance potentially excreted from the liver back to the lower GI tract via bile and/or passing unabsorbed to ultimately be excreted in faeces.

Details on distribution in tissues:

Insufficient information available

Details on excretion:

Most of the radioactivity that was excreted in urine, was associated with the metabolite NABA (11.5% of the dose). Given that the oral absorption was assigned as 14% of the dose in the review, this NABA would equate to metabolism of at least 80% of the ABA reaching the systemic circulation . The rapid drop in radioactivity in the plasma and its detection in urine, indicates that clearance of the ABA is via its metabolite NABA and is rapid and extensive.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The metabolite is N-acetyl-4-aminobenzoyl-5-alanine (NABA).

Applicant's summary and conclusion

Conclusions:

Orally dosed ABA was rapidly absorbed (most likely) from the upper GI tract, as indicated by the plasma Tmax of only 15 minutes. The extent of oral absorption was at least 14% based on comparison of urine for oral and i.v. tests. The majority (approx 80%) of the absorbed ABA was rapidly metabolised to N-acetyl-4-aminobenzoyl-5-alanine (NABA) as indicated by the relative Tmax plasma concentrations after 15 minutes. The rapid drop in radioactivity in the plasma and its detection in urine, indicates that ABA is unlikely to be distributed to body tissues and that clearance of the ABA via its metabolite NABA is rapid and extensive.