Dibutyltin maleate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented study report which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Bioorganotin Chemistry. Metabolism of Organotin Compounds in Microsomal Monooxygenase Systems and in Mammals

Author:

Kimmel EC, Fish RH & Casida JE

Year:

1977

Bibliographic source:

Journal of Agriculture and Food Chemistry, 25 (1): 1-9

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

The metabolic fate of dibutyltin acetate was examined in a microsomal monooxygenase metabolism system (MO) derived from either rat or rabbit livers. Comparative data was also provided on other alkyltins in the MO system.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

dibutyltin diacetate

IUPAC Name:

dibutyltin diacetate

Radiolabelling:

yes

Remarks:

Bu2Sn(OAc)2: 6.3 Ci/mmol

Administration / exposure

Vehicle:

ethanol

Doses / concentrations

Remarks:

Doses / Concentrations:
0.003 µmol of [14C]butyltin derivative
0.5 µmol of unlabeled compound

Results and discussion

Main ADME results

Type:

metabolism

Results:

Unlabeled Bu2SnX2 undergoes NADPH-dependent conversion to BuSnX3 (TLC cochromatography in D & E) no other products detected with rabbit microsomes, while [14C]Bu2SnX2 yields one polar NADPH-dependent metabolite and no BuSnX3with rat microsome.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

[14C]Butyltin Derivatives and Rat Liver Microsome-NADPH System:-
Metabolites of [I4C]-Bu2Sn(OAc)2 were analysed in a series of chromatographic systems that resolve all of the authentic unlabeled compounds and therefore allow tentative metabolite identification by cochromatography and quantitation by lsc. [14C]Bu2Sn(OAc)2 yields one NADPH-dependent metabolite (free, polar) in a small amount but the formation of BuSnX3does not appear to be dependent on NADPH fortification.
Unlabeled n-Alkyltin Derivatives and Rabbit Liver Microsome-NADPH System:-
Unlabeled Bu2SnX2 undergoes NADPH-dependent conversion to BuSnX3 (TLC cochromatography in D and E) but no other products are detected with rabbit microsomes, while [14C]Bu2SnX2 yields only one polar NADPH-dependent metabolite and no BuSnX3with rat microsomes.

Any other information on results incl. tables

Properties and Optimization of Monooxygenase System.

Rat liver microsomal preparations were used with ¹⁴C-labeled substrates and rabbit liver microsomes with unlabeled substrates, unless noted otherwise. With both rat and rabbit preparations, a small amount of soluble fraction (optimum 40-100 mg fresh liver weight equivalent) increases the activity of the microsome-NADPH system although the soluble fraction is not active by itself or with NADPH. There is a considerable variation in the activity of different enzyme preparations from the same species, for unknown reasons. It is necessary in all cases to fortify the microsomal preparations with NADPH to obtain detectable metabolism of the organotin and organolead substrates. (The rat liver microsome-NADPH system acting on [¹⁴C]Bu3SnOAc is totally inhibited by carbon monoxide and to a large extent by 4(5)-a-naphthylimidazole, which suggests that a cytochrome P450 dependent monooxygenase system is responsible for metabolism of the organometallic substrates.)

Applicant's summary and conclusion

Conclusions:

Metabolism of Bu2Sn(OAc)2 yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields.

Executive summary:

The metabolic fate of dibutyltin acetate was examined in a microsomal monooxygenase metabolism system (MO) derived from either rat or rabbit livers. Comparative data was also provided on other alkyltins in the MO system.

Metabolism of Bu2Sn(OAc)2 yields BuSnX3, possibly by both nonenzymatic destannylation and by a- and β-carbon hydroxylation and decomposition of the hydroxy derivatives. The unidentified polar metabolites are probably formed by two or more sites of hydroxylation at different butyl groups. Bu3SnX and Bu2SnX2 bind extensively in some tissue fractions, making analysis difficult analysis and a plausible explanation for the relatively low metabolite yields.