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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Pharmacokinetics of orally administered succinimide in man
Author:
Schulte K. E.
Year:
1978
Bibliographic source:
European Journal of Drug Metabolism and Pharmacokinetiks, No.:3, p.161-163

Materials and methods

Objective of study:
absorption
distribution
other: elimination
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The absorption and elimination of succinimide have been investigated in healthy volunteers after the oral administration of a single dose of 10 g of succinimide per person. Succinimide was spectrophotometrically determined in serum by treating succinimide with hydroxylamine at pH 8.3 and measuring the absorbance of the resultant M-hydroxysuccinimide at 260 nm.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Succinimide
EC Number:
204-635-6
EC Name:
Succinimide
Cas Number:
123-56-8
Molecular formula:
C4H5NO2
IUPAC Name:
pyrrolidine-2,5-dione
Details on test material:
no additional data available
Radiolabelling:
no

Test animals

Species:
human
Strain:
other: not applicable
Sex:
not specified
Details on test animals or test system and environmental conditions:
Three healthy volunteers. Age and weight: Nr.1: 35 years and 77 kg; Nr.2: 56 years and 95 kg; Nr.3:44 years and 65 kg.

Administration / exposure

Route of administration:
other: oral in solution (100 mL)
Vehicle:
not specified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Three healthy volunteers were given 10 g of succinimide in solution (100 mL). Concentrations have been adjusted to a dose of 10g/75 kg i.e. 0.133 g/kg. The subjects had fasted overnight.

Duration and frequency of treatment / exposure:
single administration
Doses / concentrations
Dose / conc.:
10 other: g in solution (100 mL)
No. of animals per sex per dose / concentration:
3 healthy volunteers
Control animals:
no
Positive control reference chemical:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: serum
- Time and frequency of sampling: bebore administration, 0.5, 1, 2, 4, 6, 8 and 24 hours thereafter


Statistics:
Elimination rate constants (kel) were calculated from the lines fitted, by the method of least squares , to the log blood concentration values versus time from 1 to 10 h, inclusive. The intercept gave the value of the apparent initial concentration (C0). Absorption rate constants (ka) were obtained by forcing a line through the residual concentration value at 0.5 h and the value of C0 at t=0. The maximum concentration (cmax) and the time to reach this maximum (tmax) were calculated from ka and kel as described; the fraction of the dose entering the body was assumed to be 1.

Results and discussion

Preliminary studies:
no
Main ADME resultsopen allclose all
Type:
absorption
Results:
Adsorption rate constant (ka) = 2.83 (1/h)
Type:
other: elimination serum
Results:
Elimination rate constants (kel) = 0.092 (1/h)

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Adsorption rate constant (ka) = 2.83 (1/h)
Details on distribution in tissues:
no data
Details on excretion:
no data
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
other: distribution coefficient: 0.63 ml/g
Toxicokinetic parameters:
C(time): 0h: 0.210 mg/ml
Toxicokinetic parameters:
Cmax: 0.187 mg/ml
Toxicokinetic parameters:
Tmax: 1.25 h

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
no data

Applicant's summary and conclusion

Conclusions:
Comparison of the pharmacokinetic parameter values obtained for man and for rats after the oral administration of similar doses of succinimide shows that in man absorption is faster and elimination is slower. As a consequence, the maximum blood concentration occurs earlier and is higher. The distribution coefficient lies in the range which has been determined for other water soluble drugs. An accumulation of succinimide in organs or tissues is therefore unlikely.
Executive summary:

The absorption and elimination of succinimide have been investigated in healthy volunteers after the oral administration of a single dose of 10 g succinimide per person. Succinimide was spectrophotometrically determined in serum by treating succinimide with hydroxylamine at pH 8.3 and masuring the absorbance of the resultant N-hydroxysuccinimide at 260 nm.

Comparison of the pharmacokinetic parameter values obtained for man and for rats after the oral administration of similar doses of succinimide shows that, in man absorption is faster and elimination is slower. As a consequence, the maximum blood concentration occurs earlier and is higher. The distribution coefficient lies in the range which has been determined for other water soluble drugs. An accumulation of succinimide in organs or tissues is therefore unlikely.