SILATRIZOLE

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From14 December 1994 to 20 December 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study performed the pharmacokinetics in plasma of the total radioactivity (test substance and/or metabolites), after a single oral administration by gavage.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Objective of study:

other: The objective of the study was to determine the pharmacokinetics in plasma of the total radioactivity (14C- G4375 and/or metabolites), after a single oral administration (gavage).

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study did not use a published protocol. 2 groups of 9 males were administered a single oral dose of 1000 mg/kg bw of the test substance, prepared in 2 different vehicles (0.5% aqueous solution of methylcellulose and Tween 80, or corn oil) in order to compare the absorption extent of the test substance. Sampling times after dosing were: 30 min, 1, 2, 4, 8, 24, 48 and 71 hrs (both groups) and 139 hrs (corn oil group).

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

422-940-4

EC Name:

-

Cas Number:

155633-54-8

Molecular formula:

C24H39N3O3Si3

IUPAC Name:

2-(2H-1,2,3-benzotriazol-2-yl)-4-methyl-6-[2-methyl-3-(2,2,4,6,6-pentamethyl-3,5-dioxa-2,4,6-trisilaheptan-4-yl)propyl]phenol

Test material form:

other: solid

Details on test material:

Non-radiolabeled test substance:
- Name of test material (as cited in study report): G4375
- Physical state: whitish powder
- Analytical purity: >98.8%
- Lot/batch No.: RF004
- Date of receipt: 29.11.1994
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: At room temperature and away from humidity.

Radiolabeled test substance:
- Name of test material (as cited in study report): 14C G4375 (supplied by Isotopchim)
- Physical state: whitish powder
- Analytical purity: >98%
- Lot/batch No.: 94223
- Date of receipt: 16.11.1994
- Expiration date of the lot/batch: no data
- Storage condition of test material: storage conditions: at -18°C, under nitrogen.

Radiolabelling:

yes

Remarks:

U-ring 14C labelling of the test substance molecule.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Strain Crl CD (SD) BR from Charles River France (76410 Saint-Aubin-Lès-Elbeuf, France).
- Age at study initiation: Approximately 8 weeks old
- Weight at study initiation: 309.5 ± 9.5 g
- Fasting period before study: no, food was removed just before each dosing and distributed about 4 hours thereafter.
- Housing: The animals were housed in suspended wire-mesh cages (43.0 x 21.5 x 18.0 cm) and each cage contained 3 animals of the same group. A metal tray containing autoclaved sawdust (SICSA, Alfortville, France), was placed under each cage.
- Diet (e.g. ad libitum): A04 C pelleted diet, batch Nos. 40705 (UAR, Villemoisson-sur-Orge, France), ad libitum.
- Water (e.g. ad libitum): bottles containing filtered tap water using a 0.22 micron filter (Millipore SA, Vélizy, France), ad libitum.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h/12h

IN-LIFE DATES: From: 06 December 1994 To: 20 December 1994

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 2 vehicles were used: - 0.5% aqueous solution of methylcellulose and Tween 80 (= polyoxyethylene sorbitan monooleate) = CMC+Tween 80 or - corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The isotopic mixture of 14C-G4375 and cold G4375 (specific activity: 0.011 MBq/mg of G4375) was made on the day of dosing. The day before dosing, the radiolabeled substance was dissolved in absolute ethyl alcohol and kept at -20°C under nitrogen atmosphere. On the day of dosing, radiolabelled substance was put in a mortar and non-radiolabelled substance and absolute ethyl alcohol were added in the solution until complete solubilisation, then the solution was evaporated under nitrogen. The dry isotopic mixture was suspended or dissolved in appropriate vehicle.
Total radioactivity (determined in duplicate using Liquid Scintillation System), specific activity (HPLC/UV/on-line radioactivity detection), concentration, homogeneity and identity (infra-red spectroscopy) of the test substance preparations were analysed on samples taken on the day of treatment and were found satisfactory.

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required):
. carboxymethylcellulose: batch No. 33H0576 provided by Sigma
. Tween 80: batch No. 83H0550 provided by Sigma
. Water for injections batch No. 0675 provided by Biosedra

Duration and frequency of treatment / exposure:

Single administration

Doses / concentrations

Remarks:

Doses / Concentrations:
1000 mg/kg bw

No. of animals per sex per dose / concentration:

9 males dosed with test substance in CMC 0.5% + Tween 80 and 9 males dosed with test substance in corn oil.

Control animals:

no

Positive control reference chemical:

Not used

Details on study design:

- Dose selection rationale: The dose level was determined by the sponsor, according to toxicological studies previously performed.
- Rationale for animal assignment (if not random): Before the day of treatment, the required number of males (18) were selected according to body weight and clinical condition. Cages (3 animals/cage) were not randomized in the room but placed in numerical order and vertically on the racks.
- The isotopic mixture was administered once by gavage. The quantity of the test substance administered to each animal was adjusted to the body weight recorded on the day of dosing. For each animal the administration system was weight before and after dosing in order to determine precisely the quantity administered.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : blood
- Time and frequency of sampling: two sampling time were taken per animal:
. the first three animals were sampled 30 min, 4 h and 48h after dosing,
. the second three animals were sampled 1h, 8h and 71h (and 139h after dosing for three males in corn oil group),
. the last three animals were sampled 2h and 24h after dosing.
- Other: For each group, blood samples of approximately 1 ml were taken from the orbital sinus of the animals slightly anaesthetized by ether.
Plasma levels were determined using liquid scintillation counting.

OTHER:
Clinical examination:
-Clinical signs (once a day)
-Mortality (twice a day)
-Body weight (once before dosing and on the day of dosing)
-No macroscopic examination was performed.

Statistics:

None

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The comparison of pharmacokinetics parameters showed that the absorption was more rapid in [aqueous CMC+Tween 80] than in corn oil.Plasma levels in terms of Cmax were similar in both groups (2.08 vs 1.63 µg-eq/g for CMC+Tween 80 and corn oil,respectively). These results indicate that the substance is systemically absorbed after oral administration.

Details on distribution in tissues:

The total exposure (AUC, distribution volume) was higher after administration in corn oil than in CMC + Tween 80. The AUC (0-71 hrs) was higher in the group receiving corn oil vehicle (605 µg-eq/g) as compared to the CMC-Tween 80 (384µg-eq/g), possibly due to improved absorption and/or prolonged uptake (as indicated by a longer elimination half-life: 37.3 vs 13.9 hours).

Details on excretion:

The comparison of pharmacokinetics parameters showed that the absorption and elimination were more rapid in aqueous CMC+Tween 80 than in corn oil.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

Tmax: tmax for absorption: 2 hours for the test substance in CMC+Tween 80, and approx 8 hours for the test substance in corn oil.

Toxicokinetic parameters 2

Toxicokinetic parameters:

other: Half- lives for elimination: 13.9 hrs in CMC+Tween 80 and 37.3 hrs in corn oil.

Toxicokinetic parameters 3

Toxicokinetic parameters:

AUC: 46.3 µg-eq.h/g in CMC+Tween 80 and 63.3 µg-eq.h/g in corn oil.

Toxicokinetic parameters 4

Toxicokinetic parameters:

Cmax: 2.08 vs 1.63 µg-eq/g for CMC+Tween 80 and corn oil,respectively

Toxicokinetic parameters 5

Toxicokinetic parameters:

other: Volume of distribution: 384 l/kg in CMC+Tween 80 and 605l/kg in corn oil.

Any other information on results incl. tables

Clinical examinations:
- mortality: no mortality occurred during the sampling period
- clinical signs: no clinical signs were observed during the sampling period
- body weights: there was no marked difference between both groups in term of body weight.

Applicant's summary and conclusion

Conclusions:

Interpretation of results : bioaccumulation potential cannot be judged based on study results
Under the test conditions, the absorption of the radiolabeled (14C) substance Silatrizole (G4375) was was demonstrated after single oral administration of the test substance in 0.5%aqueous CMC+Tween 80 or in corn oil.

Executive summary:

Two groups of 9 males Sprague-Dawley rats were administered a single oral dose of 1000 mg/kg bw of the radiolabeled (14C) test substance Silatrizole (G4375), prepared in 2 different vehicles (0.5% aqueous solution of methylcellulose and Tween 80, or corn oil) in order to compare the absorption extent of the test substance. Blood samples were taken at the following times, three animals per group were sampled at each time: 30 min, 1, 2, 4, 8, 24, 48 and 71 hrs (both groups) and 139 hrs (corn oil group).

 

The comparison of pharmacokinetics parameters showed that the absorption was more rapid in 0.5% aqueous solution of methylcellulose and Tween 80 than in corn oil. Plasma levels in terms of Cmax were similar in both groups (2.08 vs 1.63 µg-eq/g for CMC+Tween 80 and corn oil,respectively). These results indicate that the substance is systemically absorbed after oral administration. The AUC (0-71 hrs) was higher in the group receiving corn oil vehicle (605 µg-eq/g) as compared to the CMC-Tween 80 (384µg-eq/g), possibly due to improved absorption and/or prolonged uptake (as indicated by a longer elimination half-life: 37.3 vs 13.9 hours).

 

 

Under the test conditions, the absorption of the radiolabeled (14C) substance Silatrizole (G4375) was was demonstrated after single oral administration of the test substance in 0.5%aqueous CMC+Tween 80 or in corn oil.