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Toxicological information

Basic toxicokinetics

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basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
other information
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline and GLP not defined

Data source

Reference Type:

Materials and methods

Objective of study:
Principles of method if other than guideline:
1. Precision-cut liver slices in dynamic organ culture, is described and applied to the study of hepatic drug metabolism in the rat.
2. Precision cut Human liver slices in dynamic organ culture have been used to study the integrated metabolism .
GLP compliance:
not specified

Test material

Details on test material:
>97% radiochemical purity
not specified

Test animals

other: rat/human
other: Fischer-344

Administration / exposure

Route of administration:
not specified
Duration and frequency of treatment / exposure:
see: Any other information on materials and methods
Doses / concentrations
Doses / Concentrations:
No. of animals per sex per dose:
Control animals:
not specified

Results and discussion

Preliminary studies:
see: executive summary

Toxicokinetic / pharmacokinetic studies

Details on absorption:
see: executive summary
Details on distribution in tissues:
see: executive summary
Details on excretion:
see: executive summary

Metabolite characterisation studies

Details on metabolites:
see: executive summary

Any other information on results incl. tables

see: executive summary

Applicant's summary and conclusion

Executive summary:

1) Incubation of 0.5nM MCB withe male rat liver slices in dynamic organ culture resulted in the formation of aqueous soluble metabolites, but biotransformation activity was low. To increase the amount of metabolites formed, the number of slices per incubation was increased to three, and the volume of incubation medium was decreased from 7 to 3.5 ml. This modification resulted in only a two-fold increasein metabolism of MCB. All subsequent experiments with 0.5 mM MCB or DCB used three liver slices in 3.5 ml of incubation media. There was a time-dependent increase in the metabolism of MCB and DCB to aqueous soluble metabolites that were excreted into the incubation medium. Those metabolites retained by the slices were low and remained constant with time. Overall, the extent of metabolism of these compounds was low. At most, 5% of the added substrate was metabolized. Assessment of the sex differences in the metabolism of MCB revealed no significant differences in the extent of metabolism.Differential rates of metabolism were found between the isomers, with m->0 ->p-DCB=MCB. Differences in metabolism of the isomers could not be explained by differences in the partitioning of the parent compound into the slices. 30% of p-DCB partitioned into the slices. The percentage of total radiolabel found in the tissue for each compound was found to be constant over each 2h interval.

2) The metabolism of p-DCB to aqueous soluble metabolites:

The incubation of p-DCB with human liver slices in dynamic organ culture was carried out using the modified incubation technique employed in previous rat studies. P-DCB was incubated at a concentration of 0,5 mM with slices from three individual human livers. There was a time-dependent increase in the aqueous soluble metabolite concentration present in the medium. The levels of metabolites present in the liver slices remained constant over the incubation period.