Ethyl 2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Animal experimental study, published in peer reviewed literature

Data source

Reference

Reference Type:

publication

Title:

Zum Metabolismus von DL-trans-2-Dimethylamino-1-phenyl-cyclohex-3-en-trans-1-carbonsäureäthylester-hydrochlorid (Tilidin-HCl)

Author:

Vollmer K.O.

Year:

1977

Bibliographic source:

Arzneimittelforschung. 1977;27(9):1707-13.

Materials and methods

Objective of study:

excretion

Principles of method if other than guideline:

Metabolism and excretion of ethyl-DL-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride were investigated in rats using the radioactively labelled substance.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl trans-(±)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate hydrochloride

EC Number:

248-226-0

EC Name:

Ethyl trans-(±)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate hydrochloride

Cas Number:

27107-79-5

IUPAC Name:

27107-79-5

Constituent 2

Reference substance name:

3-Cyclohexene-1-carboxylic acid, 2-(dimethylamino)-1-phenyl-, ethyl ester, hydrochloride, (1R,2S)-rel-

IUPAC Name:

3-Cyclohexene-1-carboxylic acid, 2-(dimethylamino)-1-phenyl-, ethyl ester, hydrochloride, (1R,2S)-rel-

Details on test material:

- Name of test material (as cited in study report): DL-trans-Dimethylamino-1-phenyl-cyclohex-3-en-trans-1-carbonsäureäthylester-hydrochlorid (Tilidin-HCl, Gö 1261 C)
- Purity: 98 - 99 %

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

SIV 50

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Gödecke
- Weight at study initiation: 170 - 200 g
- Fasting period before study: yes
- Diet: no feed during the study
- Water: ad libitium

Administration / exposure

Route of administration:

other: oral gavage or intravenous

Vehicle:

water

Details on exposure:

- Animals received Tilidin-(6-14C)-HCl with an activity of 2 mCi/mMol.
- The radioactive Tilidin-HCl was diluted with normal Tilidin-HCl, to expose the test subjects to 5-10 µCi.
- Administration volume: 1 mL/100 g bw

Duration and frequency of treatment / exposure:

Single administration

Doses / concentrations

Remarks:

Doses / Concentrations:
23 mg/kg

No. of animals per sex per dose / concentration:

- intravenous administration: 12
- oral gavage administration: 8

Details on study design:

Renal excretion was measured by measuring the radioactively labelled excreted substance and metabolites in urine fractions taken in different time frames. 50% of each fraction until 24 h was pooled to get a 0-24 h urine. Metabolites were evaluated using several enzym extraction methods and thin-layer chromatography.

Details on dosing and sampling:

PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: urine was collected in the following time frames: 0-4 h, 4-8 h, 8-12 h, 12-24 h after administration.
- Before a time frame sampling animals received 1 mL/100 g bw physiologic saline.
- 50% of every timeframe fraction of urine was pooled for a 0-24 h urine.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: urine was collected in the following time frames: 0-4 h, 4-8 h, 8-12 h, 12-24 h after administration.
- Method type(s) for identification: Liquid scintillation counting, thin-layer chromatography and several enzym incubations (arylsulfatase, beta-glucuronidase)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:

- 47.1 and 51.0% of the substance administered was excreted via urine within one day of administration, after intravenous and oral gavage administration, respectively.
- Most of the excreted products were metabolites of the administered substance.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 8 h (oral gavage administration)

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 8 h (intravenous administration)

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

- Several metabolites were observed, among which nortildin and bisnortilidin.
- 17 % of the urinary radioactivity, of animals exposed via oral gavage, could be extracted with ether at alkaline pH value as so called unpolar metabolites. Of this <0.2% corresponded to the unchanged substance, 3.7% to nortilidin and bisnortilidin (<0.1% and 2.9% of applied dose, respectively).
- Ca. 25% of the urinary radioactivity, of animals exposed intravenously, could be extracted with ether at alkaline pH value as so called unpolar metabolites. Of this 7.2% corresponded to the unchanged substance, 3.7% to nortilidin and bisnortilidin (3.4% and 2.8% of applied dose, respectively).
- The largest part of the polarized metabolites were glucuronide conjugates, this was based on the incubation of the urine with different enzymes.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Executive summary:

Metabolism and excretion of ethyl-DL-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride were investigated in SIV-50 rats using the radioactively labelled substance. Following oral administration 51 % of the applied radioacitivity was eliminated via urine. After intravenous administration this elimination was 47.1%. The half-life of renal elimation, after both administration routes, was 8 h. The largest part of the administered substance was excreted as a metabolite. Several metabolites were identified, among which nortilidin and bisnortilidin. 17% of the urinary radioactivity could be extracted with ether at alkaline pH values as so called unpolar metabolites, after oral administration. After intravenous administration this was ca. 25%. The higher proportion of unchanged tilidine in the urine of the i.v. rat test in comparison to the i.g. test (3.4% and <0.1% resp. of applied dose) indicated a first-pass effect during absorption. The major part of the polarized metabolites consists of glucuronides.