Ibuprofen

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Limited information on analytical methods

Data source

Reference

Reference Type:

publication

Title:

Metabolic Chiral Inversion of 2-Arylpropionates in Rat H4IIE and Human Hep G2 Hepatoma cells - Relationship to in Vivo Metabolism

Author:

Menzel-Soglowek, S.; Geisslinger, G.; Mollenhauer, J.; Brune, K.

Year:

1992

Bibliographic source:

Biochemical Pharmacology, Vol. 43, No 7, pp. 1487-1492

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Human and rat hepatoma cell lines were used to determine capability and suitability for inversion experiments of the test substance, in which the R-form of the test substance was used as model compound. The test substance was exposed in varying conditions to determine any effects on the formation of the S-form of the test substance and on the elimination rate. Additionally, the enantiomer of the test substance was used to determine the elimination rate and the fraction inverted of the enantiomer.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ibuprofen

EC Number:

239-784-6

EC Name:

Ibuprofen

Cas Number:

15687-27-1

Molecular formula:

C13H18O2

IUPAC Name:

2-(4-isobutylphenyl)propanoic acid

Test material form:

solid

Specific details on test material used for the study:

- Name of test material (as cited in publication): R-ibuprofen (model compound, enantiomer of ibuprofen
- Supplier: Pharma Trans Sanaq AG (Basel, Switzerland)
- Purity: >98.5%

Radiolabelling:

no

Test animals

Species:

other: Rat H4IIE and Human Hep G2 Hepatoma cells

Details on species / strain selection:

The experiments were performed with existing rat- and human hepatoma cell lines.

Administration / exposure

Route of administration:

other: in solution

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

- Duration: 5 days
- Frequency: continuously

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

15 other: µg/mL

Remarks:

Main substance

Doses / concentrations 2

Dose / conc.:

30 other: µg/mL

Remarks:

Main substance

Doses / concentrations 3

Dose / conc.:

75 other: µg/mL

Remarks:

Main substance

Doses / concentrations 4

Dose / conc.:

150 other: µg/mL

Remarks:

Main substance

Doses / concentrations 5

Dose / conc.:

20 other: µg/mL

Remarks:

Enantiomer

Details on dosing and sampling:

PASSAGING
- Enantiomer: the period of passaging the cell cultures was 2 days. After, they were incubated with (the enantiomers of) the test substance.

METABOLITE CHARACTERISATION STUDIES
- Time and frequency of sampling: at ± 24, 48, 72, 96 and 120 hours
- Method type for identification: enantionmeres were identified with stereoselective HPLC method using a chiral α1 acid glycoprotein column. Metabolites were quantified by a non-stereoselective HPLC assay.

Statistics:

- Areas under data points were calculated by the linear trapezoidal rule.
- A regression equation was used to estimate the elimination rate constants of the concentration-time curves.

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The S-form of the test substance was formed by the H4IIE rat hepatoma cell line. Also hydroxylated and carboxylated forms of the test substance were observed. For additional information, see 'Any other information on results incl. tables'.

Any other information on results incl. tables

- An increase of the R-form of test substance (main substance) caused an almost linear increase (r = 0.95) in the S-form of the test substance. The elimination rate constant of the R-form of test substance was not affected.

- The number of cells and varying glucose concentrations did not influence the S-form concentrations of the test substance, whereas a reduction in serum concentration did increase its concentration. Additionally, the elimination rate constant of the R-enantiomer increased with a decreasing serum concentration.

- In addition to elimination, hydroxylation and carboxylation of the test substance was observed. The concentrations of these metabolites were low however in comparison to formation of the S-form of the test substance.

- Both the human- and rat hepatoma cell line were able to invert the R-form of the test substance.

Table: elimination rates of the R-form/S-form of the test substance after incubation with the enantiomer.

	Rat H4IIE hepatoma cells		Human Hep G2 hepatoma cells
	Elimination rate (hr-1)	Fraction inverted	Elimination rate (hr-1)	Fraction inverted
R-form test substance	0.0311 ± 0.0008	0.49	0.0035 ± 0.0001	0.26
S-form test substance	0.0015 ± 0.0001	-	0.0013 ± 0.0001	-