Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Relevance of findings unclear; source and quality of human liver microsomes cannot be judged.

Data source

Reference
Reference Type:
publication
Title:
Glucuronidation of propofol and its analogs by human and rat liver microsomes
Author:
Shimizu M, Matsumot Y, Tatsuno M, Fukuoka M
Year:
2003
Bibliographic source:
Biol. Pharm. Bull. 26; 216-219 (2003)

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
kinetic parameters for the glucuronidation of 6-tert-butyl-p-cresol and several other phenolderivatives were determined in vitro using pooled human and rat liver microsomes. Km and Vmax values were determined and compared with each other.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
no purity data, purchased from Aldrich Chem Co.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
male Wistar rats, 7-8 weeks old were anesthetized with ether and then sacrificed by exsanguination

Administration / exposure

Route of administration:
other: not applicable - rat liver microsomes were used for experiment
Vehicle:
other: not applicable
Details on exposure:
not relevant - rat liver microsomes were used for experiment
Duration and frequency of treatment / exposure:
not relevant - rat liver microsomes were used for experiment
Doses / concentrations
Remarks:
Doses / Concentrations:
not relevant - rat liver microsomes were used for experiment
No. of animals per sex per dose:
not relevant - rat liver microsomes were used for experiment
Control animals:
no

Results and discussion

Preliminary studies:
no data

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:
glucoronidation was examined using both rat liver microsomes and pooled human liver microsomes from 15 individuals (8 males and 7 females)

Any other information on results incl. tables

Rat liver microsomes werde much more active (>10 fold) at low  concentrations. 
Maximum activity in rat microsomes was ~ 2.8 nmol/min/mg protein at ~ 0.2 mM substrate, while the activity of human microsomes never exceeded 0.2 nmol/min/mg protein

Human liver microsomes:
Km: 180.7 µM
Vmax: 0.211 nmol/min/mg protein

Rat liver microsomes:
Km: 17.3 µM
Vmax: 3.06 nmol/min/mg protein

Applicant's summary and conclusion

Executive summary:

method: kinetic parameters for the glucuronidation of 6 -tert-butyl-p-cresol and several other phenolderivatives was determined in vitro using pooled human and rat liver microsomes. Km and Vmax values were determined

result: glucuronidation of 6 -tert-butyl-p-cresol is in rat liver microsomes greater than in human pooled liver microsomes

reference: Shimizu, 2003