Climbazole

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1980-09-22 (report date)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted neither as per any regulatory guideline nor GLP regulation.

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:

1980

Report date:

1980

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Concentrations of crinipan (climbazole) and of its metabolite (BAY g 5919) in blood plasma of beagle dogs treated orally with BAY e 6975 were determined on days 1, 47 and 92 of a sub-chronic toxicity study. The daily dose was 5, 10 and 20 mg/kg, respectively.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Climbazole

EC Number:

253-775-4

EC Name:

Climbazole

Cas Number:

38083-17-9

Molecular formula:

C15H17ClN2O2

IUPAC Name:

1-(4-chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutan-2-one

Radiolabelling:

no

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

12 male and 12 female beagle hounds with a mean body weight of 9.5 kg (range: 7.7 to 11.4 kg) were included in this study.

Administration / exposure

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Details on exposure:

The substance was administered in gelatine capsules and the control group received empty gelatine capsules.

Duration and frequency of treatment / exposure:

The test animals were weighed weekly; the daily single doses were adjusted for 7 d to the body weight as last determined. The administration took place over a period of 13 weeks, once daily, on all seven days of the-week, about 1 h before the daily feeding. After administration the animals were observed for another 10 min in order to readminister capsules that may have been vomited up or spat out.

Doses / concentrations

Remarks:

Doses / Concentrations:
Daily dose were 5, 10 and 20 mg/kg

No. of animals per sex per dose / concentration:

3 animals per sex per group i.e. 6 animals per group

Control animals:

yes

Positive control reference chemical:

not applicable

Details on study design:

Concentrations of crinipan (BAY e 6975) and of its metabolite (BAY g 5919) in blood plasma samples were determined using thin-layer densitometric method.

Details on dosing and sampling:

Blood sampling for the determination of the concentrations of the active substance in plasma was carried out at 4 and 24 h post-administration, on test days 1, 47 and 92. On the 47th test day also blood was taken in addition before the administration (= 24 h after the 46th dose).

Statistics:

Concentrations of crinipan and metabolite were calculated using the calibration curves based on the serum standards of the same plate.

Results and discussion

Preliminary studies:

In almost all 24 h samples of the three days of investigation, as well as in the plasma of the additionally taken blood samples before administration on the 47th test day (= 24 h after the 46th dose) the concentrations of the unchanged substance and metabolite were below the determination limit of 10 ng/ml.
The concentrations of BAY e 6975 in the plasma 4 h after administration were on average on the three days of investigation:
in the 5 mg group between 17, 36, and 34 ng/mL, respectively
in the 10 mg group between 47, 94, and 97 ng/mL, respectively
in the 20 mg group between 357, 234 and 167 ng/mL, respectively
and thus show that the high dose also results in a higher concentration of the active substance: in the plasma. The concentrations of BAY e 6975 in the plasma were very low, however, compared to the dose administered. The mean equipartition concentrations P [P= Concentration in plasma (mg/L) / Dose (mg/kg)] at the time 4 h after administration were between 0.008 and 0.018; even assuming a plasma level maximum 2 h after administration with twice as high concentration values, this means that in the dog more than 95% of the administered dose was metabolized in the first pass metabolism, whereby among other substances, BAY g 5919 was formed. The 4 h plasma levels of metabolite BAY g 5919 were on average 2 to 5 times higher than those of the unchanged substance.

Main ADME results

Type:

metabolism

Results:

In the dog more than 95% of the administered dose was metabolized in the first pass metabolism (main metabolite was a secondary alcohol).

Toxicokinetic / pharmacokinetic studies

Details on absorption:

no data

Details on distribution in tissues:

no data

Details on excretion:

no data

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolite BAY g 5919 (secondary alcohol)

Any other information on results incl. tables

not applicable

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: In the dog more than 95% of the administered dose was metabolized in the first pass metabolism, whereby among other substances BAY g 5919 was formed
Crinipan plasma levels in dogs treated orally with 5, 10, 20 mg/kg/day for 90 days were low compared with the dose administered, indicating a pronounced first pass metabolism (>95% of parent compound was metabolised). Concentrations of the metabolite (a secondary alcohol) exceeded those of the parent drug by a factor of 2 to 5. 24 h after substance administration, concentrations of both parent compound and metabolite were less than 10 ng/mL (detection limit).

Executive summary:

Concentrations of crinipan (BAY e 6975) and of its metabolite (BAY g 5919) in blood plasma of beagle dogs treated orally with crinipan were determined on days 1, 47 and 92 of a sub-chronic toxicity study. The daily dose was 5, 10 and 20 mg/kg, respectively were administer to 3 male and 3 female dogs per group with a mean body weight of 9.5 kg (range: 7.7 to 11.4 kg). Concentrations of crinipan and BAY g 5919 were determined using thin-layer densitometric method. Crinipan plasma levels in all three dosage group 4 h after application, were low compared with the dose administered, indicating a pronounced first pass metabolism. Concentrations of the BAY g 5919 (secondary alcohol) however exceeded those of the crinipan by a factor of 2 to 5. After 24 h of drug administration, concentrations of both crinipan and metabolite were less than 10 ng/mL (determination limit).