Fluocortolone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: expert statement

Adequacy of study:

other information

Study period:

not applicable

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well reported expert statement

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Objective of study:

other: pharmacokinetic

Test guideline

Deviations:

not applicable

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Fluocortolone

EC Number:

205-811-5

EC Name:

Fluocortolone

Cas Number:

152-97-6

Molecular formula:

C22H29FO4

IUPAC Name:

(1S,2R,3aS,3bS,5S,9aR,9bS,10S,11aS)-5-fluoro-10-hydroxy-1-(2-hydroxyacetyl)-2,9a,11a-trimethyl-1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-7-one

Details on test material:

- Name of test material (as cited in study report): fluocortolone (ZK 10445)

Radiolabelling:

yes

Remarks:

using ³H-FC with the tritium-label in position 1, 2 and 4 of ring A

Test animals

Species:

human

Strain:

other: not applicable

Sex:

not specified

Administration / exposure

Route of administration:

other: oral and intravenous

Vehicle:

not specified

Duration and frequency of treatment / exposure:

single

Doses / concentrations

Remarks:

Doses / Concentrations:
oral: 10 and 20 mg/person
iv: no data

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

oral: bioavailability was 77.4 +/-17.8% and 89.0 +/- 29.4%, respectively, after 10 and 20 mg oral absorption

Main ADME results 2

Type:

metabolism

Results:

Oxidation of the hydroxy-group on C11, reduction of the keto-group on C20, hydroxylation at 6ß-position under defluoronation, carbonylic acid production under oxidation of the keto-group on C20 and conjugation with glucuronic acid and sulfuric acid.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral: bioavailability was 77.4 +/-17.8% and 89.0 +/- 29.4%, respectively, after 10 and 20 mg oral application in human

Details on distribution in tissues:

no data

Details on excretion:

completely with the urin, mainly as metabolites

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: plasma: 1.5 hours after iv application

Toxicokinetic parameters 2

Toxicokinetic parameters:

half-life 1st: plasma: 1.7 hours after oral application

Toxicokinetic parameters 3

Toxicokinetic parameters:

other: total clearance: 7.0 +/- 1.5 ml/min/kg

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Reactions of biotransformation were oxidation of the hydroxy-group on C11, reduction of the keto-group on C20, hydroxylation at 6ß-position under defluoronation, carbonylic acid production under oxidation of the keto-group on C20 and conjugation with glucuronic acid and sulfuric acid.

Any other information on results incl. tables

The plasma half-life of fluocortolone and metabolites is approx. 4 hours.

Applicant's summary and conclusion

Conclusions:

No bioaccumulation potential based on study results.

Fluocortolone is readily bioavailable in the blood and almost completely metabolised in the liver.

Metabolites are excreted via the urine.

Executive summary:

After intravenous application of fluocortolone in human the half-life in the plasma was determined with 1.5 hours. The total clearance was 7.0 +/- 1.5 ml/min/kg and is equivalent to the metabolic clearance since fluocortolone is almost completely metabolised and only a small amount of this substance is found in the urin.

After oral application of 10 mg and 20 mg fluocortolone to human the maximum plasma level was reached after 1.5 hours. The total bioavailability was 77.4% +/-17.8% and 89.0% +/- 29.4%, respectively. The plasma half-life is 1.7 hours. Fluocortolone is metabolised in the human liver and the metabolites are excreted with the urine. Reactions of biotransformation were oxidation of the hydroxy-group on C11, reduction of the keto-group on C20, hydroxylation at 6ß-position under defluoronation, carbonylic acid production under oxidation of the keto-group on C20 and conjugation with glucuronic acid and sulfuric acid. The plasma half-life of fluocortolone and metabolites is ca. 4 hours.