(R,R)-(-)-butane-2,3-diol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1993

Materials and methods

Objective of study:

absorption

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study investigated the metabolism of the individual isomers of 2,3-butanediol (2R,3R-, 2S,3S-, meso-2,3-butanediol and racemic 2,3-butanediol) in perfused livers from fed rats.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

(R,R)-(-)-butane-2,3-diol

EC Number:

246-186-9

EC Name:

(R,R)-(-)-butane-2,3-diol

Cas Number:

24347-58-8

Molecular formula:

C4H10O2

IUPAC Name:

(R,R)-(-)-butane-2,3-diol

Test material form:

liquid

Specific details on test material used for the study:

- 2R,3R (levo) and 2S,3S (dextro) 2,3-butanediol were obtained from Aldrich Chemical Co.
- Racemic 2,3-butanediol was purchased from Pfaltz and Bauer, Waterbury, CN.
- Meso-2,3-butanediol was obtained from Fluka Chemical Corp., Ronkonkoma, NY.

Radiolabelling:

yes

Remarks:

2H, 14C

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

For liver perfusion experiments:
Male Sprague-Dawley rats (Charles River Laboratories) were fed ad libitum with Purina rat chow. For the series of liver perfusions with unlabelled isomers of butanediol, the rats weighed 210-300 g. For the series of perfusions with radio labelled butanediols, the rats weighed 160-210 g.

Administration / exposure

Route of administration:

other: ex vivo (liver perfusion)

Statistics:

Data were analysed by one-way ANOVA, followed by the Bonferroni test to identify significant differences between groups. Perfusions with labelled 2,3-butanediol were analysed separately from perfusions with unlabelled 2,3-butanediol because of the difference in weights of rats. Significance level was set to p < 0.05.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Uptake of the 2,3-butanediol isomers decrease in the order: levo > meso > dextro.

Main ADME results 2

Type:

metabolism

Results:

Levo and meso 2,3-butanediol metabolise to acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3- butanediol is oxidized to acetyl-coA via acetoin.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Analysis of control liver perfusates from fed rats indicated that any endogenous production of 2,3-butanediol or acetoin was below LOD of the assay (1 µM). In a preliminary perfusion experiment with 20 mM ethanol, neither acetoin nor butane-2,3-diol was produced during the first hour. However, when 5 mM pyruvate was added, acetoin and 2,3-butanediol accumulated up to 15 µM over the second hour. Presence or absence of butane-2,3-diol isomers did not affect the uptake rate of any individual isomer.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Differences were observed in the metabolism of individual 2,3-butanediol isomers in perfused rat liver. Interconversion of isomers and oxidation to acetoin was observed with levo and meso, but not with dextro 2,3-butanediol.
In liver perfusions with either levo or meso (radiolabelled) 2,3-butanediol, the substrates were converted to labelled acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3-butanediol was oxidized to acetyl-CoA via acetoin. Production of radio-labelled CO2, acetate, ketone bodies, acetoin, and other isomers of butane-2,3-diol accounted for approximately one-third of the label uptake.

Applicant's summary and conclusion

Conclusions:

Absorption: Uptake of 2,3-butanediol isomers decrease in the order: levo > meso > dextro.
Metabolism: Levo and meso 2,3-butanediol metabolise to acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3- butanediol is oxidized to acetyl-coA via acetoin.

Executive summary:

Montgomery et al. 1993 investigated the metabolism of the individual isomers of 2,3 -butanediol (levo (2R,3R), dextro (2S,3S), meso 2,3 -butanediol and racemic 2,3 -butanediol) in perfused livers from fed rats. Differences were observed in the metabolism of individual 2,3-butanediol isomers in perfused rat liver. Interconversion of isomers and oxidation to acetoin was observed with the levo and meso forms, but not with dextro 2,3-butanediol. In liver perfusions with either levo or meso (radio-labelled) 2,3-butanediol, the substrates were converted to labelled acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3-butanediol was oxidized to acetyl-CoA via acetoin.