1H-Indene-1,3(2H)-dione, 2-(2-quinolinyl)-, sulfonated, sodium salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Remarks:

Study of biliary excretion in isolated perfused liver

Type of information:

experimental study

Adequacy of study:

weight of evidence

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:

Studies on the Fate of Quinoline Yellow in the Rat

Author:

Wahlstrom B., Blennow G. and Krantz C.

Year:

1979

Bibliographic source:

Food and Cosmetics Toxicology, 17, pp 1-3

Materials and methods

Objective of study:

metabolism

other: Biliary excretion

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

- Principle of test: rats’ isolated liver was perfused with the test item added to the perfusion fluid. Biliary excretion was studied.
- Short description of test conditions: Animals used for studying biliary excretion in the isolated perfused liver were anaesthetized. The common bile duct was cannulated and the liver was dissected and connected to an artificial sys tem containing human erythrocytes and bovine albumin in a physiological salt solution. The volume of the perfusion fluid was 75 ml, the temperature was 37°C and the pH was 7.4. The test item was added to the perfusion fluid dissolved in 0.9% NaCI. Bile and perfusion fluid were sampled at regular intervals during the experiment. The perfusion usually lasted 3 hours.
- Parameters analysed/observed: Concentration of the test item in the perfusion fluid and in the bile and bile flow at different time’s interval.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1H-Indene-1,3(2H)-dione, 2-(2-quinolinyl)-, sulfonated, sodium salts

EC Number:

305-897-5

EC Name:

1H-Indene-1,3(2H)-dione, 2-(2-quinolinyl)-, sulfonated, sodium salts

Cas Number:

95193-83-2

Molecular formula:

C18H11NO5S to C18H8NO11S3.3Na

IUPAC Name:

trisodium hydrogen bis(2-(1,3-dioxo-5-sulfonato-2,3-dihydro-1H-inden-2-yl)quinoline-8-sulfonate)

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Rats were SPF-bred.
- Weight at study initiation: 200 – 300 grams.
- Housing: Rats were maintained in special animal unit with strict hygienic barriers before the experiments.
- During the experiment the animals were anaesthetized with diethyl ether.

Administration / exposure

Route of administration:

other: Perfusion of isolated liver

Vehicle:

other: The test item was dissolved in 0.9% NaCl and added to the perfusion fluid (10-12% human erythroctìytes and 2.5% bovine albumin in a physiological salt solution.

Details on exposure:

The test item was dissolved in 0.9% NaCl solution and added to the perfusion fluid (10-12x human erythrocytes and 25% bovine albumin in a physiological salt solution).
Concentration of the test item in the perfusion fluid: 25 mg/100 mL
Volume of the perfusion fluid: 75 ml
Temperature of the perfusion fluid: 37°C
pH of the perfusion fluid: 7.4.

Duration and frequency of treatment / exposure:

The perfusion usually lasted 3 hours.

Doses / concentrations

Dose / conc.:

25 other: mg/100 mL of perfusion fluid

No. of animals per sex per dose / concentration:

6 animals in total were used. The numebr of females and males was not specified.

Control animals:

not specified

Positive control reference chemical:

Not specified.

Details on dosing and sampling:

- Body fluid sampled: bile
- Time and frequency of sampling: the bile and the perfusion fluid were sampled several times during the 3 hours perfusion duration.
- Method type for identification: the test item in the bile was determined after extraction with 0.1 M HCI at 418 nm on a Beckman DB-25 spectrophotometer. The spectra of the test item extracted from bile were checked against those of test item standard solutions in 0.1 M HCI.

Statistics:

Values are presented as means ± SEM.

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

About 70% of the administered dose was excreted into the bile within 3 hours. The maximum concentration of the test item in the bile, 30-50 mg/mL, was found after about 30 minutes.

Main ADME results 2

Type:

metabolism

Results:

The recovery of the test item from perfusion fluid and bile was almost quantitative (about 95%), showing that the test item was not significantly metabolized.

Toxicokinetic / pharmacokinetic studies

Details on excretion:

After addition of the test item to the isolated perfused liver, about 70% of the administered dose was excreted into the bile within 3 hours. The excretion was rapid and the maximum concentration of the test item in the bile, 30-50 mg/mL, was found after about 30 minutes.

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

The concentration of the test item in the perfusion fluid decreased concomitantly with increasing biliary excretion and the recovery of the test item from perfusion fluid and bile was almost quantitative (about 95%), showing that the test item was not significantly metabolised.

Any other information on results incl. tables

The test item did not affect blood flow through the perfused liver, but the bile flow was always slightly increased during the first 30 minutes after administration.

Effect of the test item on the drug-metabolising system in the liver microsomes: The activities of N-aminopyrine demethylase and aniline hydroxylase were determined in livers taken from the perfusion experiments. There were no differences between the enzyme activities of microsomes from control and treated livers.

Experiment	No. of animals	Duration (hours)	Recovery (% of administered dose)		Total recovery (%)
			Bile	Blood (perfusion fluid)
Perfused isolated liver	6	3	67 ± 6	26 ± 4	93 ± 3

Applicant's summary and conclusion

Conclusions:

After addition of the test item to the isolated perfused liver, about 70% of the administered dose was excreted into the bile within 3 hours. The excretion was rapid and the maximum concentration of the test item in the bile, 30-50 mg/mL, was found after about 30 minutes. The recovery of the test item from perfusion fluid and bile was almost quantitative (about 95%), showing that the test item was not significantly metabolised.

Executive summary:

6 anaesthetized rats were used for studying biliary excretion in an isolated perfused liver system. The test item was added to the perfusion fluid. Bile and perfusion fluid were sampled at regular intervals during the experiment. The perfusion usually lasted 3 hours. After addition of the test item to the isolated perfused liver, about 70% of the administered dose was excreted into the bile within 3 hours. The excretion was rapid and the maximum concentration of the test item in the bile was found after about 30 minutes. The recovery of the test item from perfusion fluid and bile was almost quantitative (about 95%), showing that the test item was not significantly metabolised.