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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
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:
Unnamed
Year:
1983

Materials and methods

Objective of study:
bioaccessibility (or bioavailability)
distribution
excretion
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
2 animals/dose
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Citicoline
EC Number:
213-580-7
EC Name:
Citicoline
Cas Number:
987-78-0
Molecular formula:
C14H26N4O11P2
IUPAC Name:
(2-{[({[(2R, 3S, 4R, 5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl] methyl phosphonato}oxy)(hydroxy)phosphoryl]oxy}ethyl)trimethylazanium
Details on test material:
Synonym: CDP-Choline
Specific details on test material used for the study:
RADIOLABELLING INFORMATION
CDP-choline was prepared by the Radiochemical Center of Amercham by an enzymatic process from phosphoryl (14C-methyl) choline and cytidine 5'-triphosphate.
- Radiochemical purity: It was purified by ionic exchange chormatography and the radiochemical purity was determied to be 99%.
- Specific activity: it was 50 mCi/mol
- Locations of the label: (14C-methyl) choline

Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: own colony
- Weight at study initiation: 175-225 g
- Housing: metabolic cages
- Diet: fasted up to 24h after administration and then with free access to food
- Water: ad libitum
- Fasting period: 16-h prior to administration.

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: in a solution not specified
Duration and frequency of treatment / exposure:
Administered only in one occasion into jugular vein.
Doses / concentrations
Dose / conc.:
4 mg/kg bw (total dose)
Remarks:
with an activity of 10 microCi per animal
No. of animals per sex per dose / concentration:
2
Control animals:
not specified
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled:
Blood samples (about 100 ml) were obtained by means of small cuts in the tail at the scheduled times and evaluated by weighing.
Urine and feces produced in the periods of 0-24h and 24-72h were collected.
The organs studied were brain, lung, kidney, liver and heart. The animals used fo the determination of organ levels were collected under anesthesia with ether before the extraction of the respective organ. The organs were immediatelly and carefully removed. Aliquot parts of 100 mg of tissue were digested and decolorised. Then, they were measured in the scintillation counter.
- Other:
Blood was put to digest decolorise in a mixture of hydrogen peroxide and Packard soluene-isopropanol before being counted in a liquid scintillation counter LS-7500 Beckman in the presence of 10 ml of Instagel-0.5 N HCl, according to the programme for 14C-counting.
Urines were diluted in to water up to a volume of 50 ml.
Feces were homogenized and diluted up to a volume of 250 ml.
From the diluted urine and feces, sampels of 1 ml were taken as to evaluate them with scintillation counter in the presence of Instagel, according to the prgramme for 14C.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, blood, brain, lung, kidney, liver and heard tissues.
- Method type(s) for identification: The samples were counted with a liquid scintillation counter LS-750, according to the programme for 14C.

Results and discussion

Main ADME resultsopen allclose all
Type:
distribution
Results:
CDP-choline and metabolites are widely distributed
Type:
excretion
Results:
inestimable by fecal route and low by urinary route

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
A fall in values of the radioactivity corresponding to CDP-choline administered by intravenous route is observed between 1/2 and 1 hour after administration. Later, on the blood concentration shows a trend to come back slowly to the initial values. Thus, a redistribution phase is made evident.

CDP-Choline or its labelled metabolites are widely distributed, the cerebral radioactivity evolving in a different way from the blood which would confirm the inclusion of the product in the pool of phospholipids.
Details on excretion:
The elimination is inestimable by fecal route and low by urine route, giving rise to the high hematic levels obtained at long times.

The values obtained ranged between 6-7% of total recovery, corresponding to a large degreee to the urinary elimination. An important percentage is eliminated in the form of CO2. Moreover, it seems taht there is a fixation of CDP- Choline or its metabolites in the structure components of the blood such as a red blood corpuscles and leukocytes, because these products are problably included in the metabolic processes of inclusion in cellular structures.
Toxicokinetic parameters
Key result
Test no.:
#1
Toxicokinetic parameters:
AUC: 77.42
Remarks:
0-24 h

Metabolite characterisation studies

Metabolites identified:
not measured

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
The CDP-choline is completely absorbed when administered by intravenous route. The bioavailability is practically complete.

Any other information on results incl. tables

Table 1: Bood kinetics of the total radioactivity after intravenous administration of 4 mg/kg of CDP-Choline to male rats, expressed as percentage of radioactivity per 10 ml of blood, as average and standard deviation:

Time

Average

Standard deviation

10 min

3.05

0.24

20 min

2.59

0.31

30 min

1.47

0.22

1 h

1.40

0.02

2 h

2.84

0.02

3 h

2.50

0.05

4 h

2.77

1.00

5 h

3.37

0.31

6 h

3.68

0.02

7 h

-

-

24 h

3.12

0.19

Table 2: Urinary and fecal recovery of radioactivity after the administration of 4 mg/kg of CDP-choline intravenously, as percentage related to the administered dose, expressed as the average with standard deviation:

Urine/fecal collection period

Average

Standard deviation

0-24

1.78

0.38

24-72

4.84

0.61

0-24

0.12

0.10

24-72

0.56

0.23

Table 3: Organic distribution of CDP-Choline and labelled metabolites, expressed as percentage of total dose, after intravenous administration of 4 mg/kg of labelled CDP-choline:

Time

5 h

24 h

 

Average

Standard Deviation

Average

Standard Deviation

Brain

0.26

0.03

0.23

0.18

Lung

2.27

0.29

2.32

1.68

Liver

2.32

6.82

15.52

6.81

Kidney

5.86

1.61

1.45

0.98

Heart

0.85

0.72

1.03

0.87

Applicant's summary and conclusion

Conclusions:
The CDP-choline administered by intravenous route on rats is widely distributed in the organs and eliminated very slowly. The value of AUC (0-24h) is 77.42.
Executive summary:

The bioavailability of radiollableled CDP-choline was studied by intravenous route on Sprague-Dawley rats. The amount of 4 mg/kg bw (total dose) was administered in a solution into jugular vein and the absortion, distribution on brain, lung, kidney, liver and heart and excretion of the substance was evaluated. The product was widely distributed in the organs and a very low urinary and fecal elimination was observed, thus producing mantained blood levels. The AUC (0-24h) was determined to be 77.42.