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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
Objective of study:
absorption
distribution
other: elimination
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
Radiolabelling:
no
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.
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
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.
Preliminary studies:
no
Type:
absorption
Results:
Adsorption rate constant (ka) = 2.83 (1/h)
Type:
other: elimination serum
Results:
Elimination rate constants (kel) = 0.092 (1/h)
Details on absorption:
Adsorption rate constant (ka) = 2.83 (1/h)
Details on distribution in tissues:
no data
Details on excretion:
no data
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
Metabolites identified:
not measured
Details on metabolites:
no data
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.

Endpoint:
basic toxicokinetics in vivo
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
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
Only Abstract of publication is available, no information about guideline.- Principle of test: Pharmacokinetics and disposition of orally administered radiolabeled succinimide in the rat
- Short description of test conditions: The absorption, distribution, and elimination of radioactivity after the oral administration of 14C-Iabelled succinimide has been investigated at three dosage levels (0.09, 1.0 and 2.0 g/kg).
- Parameters analysed / observed: A comparison was made of the blood concentration of radioactivity after the intraperitoneal and oral administration of 0.5 g/kg of succinimide. The pharmacokinetics of orally administered succinimide have been fitted to a one-compartment open model
GLP compliance:
no
Specific details on test material used for the study:
RADIOLABELLING INFORMATION (if applicable)
A mixture of [2,3-14C] succinic acid (5 mCi; 250 mg; radiochemical purity 97%. The Radiochemical Centre Ltd, Amersham), inactive succinic acid (40 g, 0.34 mole), and tertiary ammonium phosphate (0.4 g) in 25% aqueous ammonia solution (43.4 ml, 0.51 mole) was shaken for two hours at room temperature and then heated to 250 °C, with occasional shaking. This temperature was maintained until the water had evaporated. Succinimide was removed by sublimation (l24 °C, 5 mm Hg) and was recrystallized from acetone. Yield of succinimide: 22.5 g (68%), m.p. 123-124°C. Specific activity: 1.367 mCi/mmol.
Radiolabelling:
yes
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Tierzuchtanstalt Wilndrich, Altenberge

- Age at study initiation: no data
- Weight at study initiation: 150-220 g (not fasted; food was removed about 1 h before drug administration); 100-120 g (fasted rats; for the comparison of intraperitoneal and oral administration of succinimide; food was removed 16-18 h before drug administration
- Housing: The rats were placed into metabolism cages for the collection of urine and faeces, or of expired air

- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: gavage
Vehicle:
other: aqueous solution
Duration and frequency of treatment / exposure:
single treatment
Dose / conc.:
90 mg/kg bw/day
Remarks:
oral administration of 14C-labelled succinimide
Dose / conc.:
500 mg/kg bw/day
Remarks:
for comparison of the bloss concentration of radioactivity after i.p. and oral administration
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
oral administration of 14C-labelled succinimide
Dose / conc.:
2 000 mg/kg bw/day
Remarks:
oral administration of 14C-labelled succinimide
No. of animals per sex per dose / concentration:
no data
Control animals:
not specified
Positive control reference chemical:
not applicable
Details on study design:
no data
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma,
METABOLITE CHARACTERISATION STUDIES
Rats were killed 2, 4, 8 and 24 h after the oral administration of 14C-succinimide (1.0 g/kg), or 48 and 72 h after the oral administration of 2.0 g/kg. The plasma obtained after addition of HCI and centrifugation was lyophilized and then extracted with methanol. The methanol extract was concentrated and applied to TLC plates and developed in TLC solvent systems I and II.
The calculation of pharmacokinetic parameters followed the methods described by Wagner. Lines were fitted by the method of least squares.

Radioactivity measurements:

Radioactivity was determined with either a Nuclear Chicago Isocap/300 Model 6868 liquid scintillation spectrometer or a Berthold LB 2721 radiochromatogram scanner. Quench correction for liquid scintillation counting was made by internal standardization with 14C-toluene. Samples of blood or plasma, or rehydrated, homogenized organs or faeces, were digested in Soluene 350 (Packard), decolourized with H202/isopropanol and counted in Permablend III (Packard). Samples of the 2-phenylethylamine/methanol mixture used to trap CO2 in expired air or from the combustion of faeces, were counted in Permablend III. Samples of urine or methanol extracts were counted in the dioxane based scintillator, Diotol (Packard). The radioactivity on thin-layer and preparative chromatograms was detected with a radiochromatogram scanner. For quantitative measurement, zones of the thin-layer plates were scraped off and the radioactivity determined in a liquid scintillation mixture (Diotol or Instagel).
Statistics:
The pharmacokinetics of orally administered succinimide have been fitted to a one-compartment open model.
Type:
absorption
Results:
see Table 1 in box "Any other information on results incl. tables".
Type:
distribution
Results:
see Table 1 in box "Any other information on results incl. tables".
Type:
excretion
Results:
see Table 1 in box "Any other information on results incl. tables".
Type:
metabolism
Results:
see Table 2 in box "Any other information on results incl. tables".
Details on absorption:
Maximum blood concentrations were seen after about 2 h.
Absorption and elimination were faster after dosage at 0.09 g/kg than after 1.0 and 2.0 g/kg.
Succinimide appeared to be well absorbed, and was evenly distributed throughout the body.
Details on distribution in tissues:
Succinimide appeared to be well absorbed, and was evenly distributed throughout the body.
Details on excretion:
About 70 % of an administered dose of 1.0 g/kg was eliminated within 32 h: 50 % in urine, 4 % in the faeces, and 17 % as 14CO2 in the expired air.
Metabolites identified:
no

Table 1: Pharmacokinetic properties after oral administration of 14C-succinimide in rats

  Dose (g/kg)
  0.09 1.0 2.0
Absorption      
ka(1/h) 1.5 0.90 1.11
t1/2a(h) 0.46 0.77 0.63
Elimination      
kel(1/h) 0.151 0.134 0.118
t1/2el(h) 4.59 5.17 5.87
Apparent initial concentration      
C0(mg/mL) 0.137 1.127 2.634
Apparent volume of distribution      
Vd(1/kg) 0.66 0.89 0.76
Apparent total clearance      
Vdx kel(1/h) 0.10 0.12 0.09
Maximum blood concentration      
cmax(mg/mL) 0.106 0.807 2.017
Time to cmax      
tmax(h) 1.7 2.49 2.26

Table 2: Relative amounts of succinimide and metabolites eliminated in urine up to 72 h after oral administration of 14C-succinimide

  Radioactivity (% of total) Relative amount of radioactivity in urine (0-24 h = 100)
Time interval (h) Succinimide  Metabolites
0-24 89 5 100
24-48 76 15 8
48-72 73 20 3
Conclusions:
Maximum blood concentrations were seen after 2 h. Succinimide was well absorbed and evenly distributed throughout the body.
About 70 % of an administered dose of 1.0 g/kg was eliminated within 32 h: 50 % in urine, 4 % in the faeces, and 17 % as 14CO2 in the expired air.
Executive summary:

The absorption, distribution, and elimination of radioactivity after the oral administration of 14C-labelled succinimide has been investigated at three dosage levels (0.09, 1.0, and 2.0 g/kg). A comparison was made of blood concentration of radioactivity after the intraperitoneal and oral administration of 0.5 g/kg of succinimide. The pharmacokinetics of orally administered succinimide have been fitted to a one-compartment open model.

Maximum blood concentrations were seen after 2 h. Succinimide was well absorbed and evenly distributed throughout the body.

About 70 % of an administered dose of 1.0 g/kg was eliminated within 32 h: 50 % in urine, 4 % in the faeces, and 17 % as 14CO2 in the expired air. Approximately 90 % of the radioactivity in the urine (0 -24 h) was succinimide.

Description of key information

Rat

The absorption, distribution, and elimination of radioactivity after the oral administration of 14C-labelled succinimide has been investigated at three dosage levels (0.09, 1.0, and 2.0 g/kg). A comparison was made of blood concentration of radioactivity after the intraperitoneal and oral administration of 0.5 g/kg of succinimide. The pharmacokinetics of orally administered succinimide have been fitted to a one-compartment open model.

Maximum blood concentrations were seen after 2 h. Succinimide was well absorbed and evenly distributed throughout the body.

About 70 % of an administered dose of 1.0 g/kg was eliminated within 32 h: 50 % in urine, 4 % in the faeces, and 17 % as 14CO2 in the expired air. Approximately 90 % of the radioactivity in the urine (0 -24 h) was succinimide.

 

Human (males)

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 measuring 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.

Key value for chemical safety assessment

Additional information