Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-,C12-13-branched alkyl esters

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Secondary sources assessed to provide reliable background information related to chemical groups/classes

Justification for type of information:

QSAR prediction

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Unnamed

Year:

1998

Report date:

1998

Reference 2

Reference Type:

review article or handbook

Title:

Alkohole, Ether, Ester

Author:

Eisenbrand G, Metzler M

Year:

2002

Bibliographic source:

Toxikologie für Naturwissenschaftler und Mediziner. Wiley-VCH, Weinheim, Germany, 2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Compilation of accepted pharmacological and toxicological principles for the substance classes of esters, alcohols, and acids

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-,C12-13-branched alkyl esters

EC Number:

947-004-7

Molecular formula:

C28H56O6 - C29H58O6 - C30H60O6

IUPAC Name:

Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-,C12-13-branched alkyl esters

Test material form:

liquid

Details on test material:

product

Results and discussion

Any other information on results incl. tables

Absorption

In general, branched-chain aliphatic acyclic esters, alcohols, aldehydes and acids are rapidly absorbed from the gastrointestinal tract (Semino 1998a, b).

 

Biotransformation

Esters

Esters are rapidly hydrolysed in vivo in various organs by ubiquitous esterases. Hydrolysis occurs already in the gastrointestinal tract and proceeds in blood, liver, and other organs (Semino 1998a).

Alcohols

Alcohol dehydrogenase pathway

Long chain saturated primary alcohols undergoe oxidation by alcohol dehydrogenase (ADH) to the corresponding aldehyde followed by further oxidation by aldehyde dehrogenase (AlDH) to isododecanoic acid and isotridecanoic acid. The oxidation rate depends on the Michaelis constant (Km) of the alcohol for the reaction catalyzed by ADH. The Km values depend on the chain length (Km: C2< C1, C3<C4<C5<C6<C7<C8<C9<C10 etc.) and possibly also on steric hindrance due to bulky side chains (Eisenbrand & Metzler, 2002).

Alternative pathways

The proportion of alternative pathways increases with decreasing affinity to ADH (and, therefore, low reaction rates), and increasing dose, chain length and branch grade. Then, chain oxidations (omega- or omega-1oxidation) result in polyols which may be further oxidized to carbonic or dicarbonic acids, or keto acids, etc..

Acids

Branched carboxylic acids can undergoe degradation via ß-oxidation preferably in the longer chain to yield shorter fragments. These can be further metabolised in the fatty acid pathway and the citrate cycle. ß-Oxidation and further usage in the citrate cycle proceeds easily for linear alcohols and branched alcohols bearing a methyl group/alkyl substituent at even positions. Methyl groups(alkyl substituents at uneven positions, inhibit ß-oxidation, which favours alternative metabolic pathways (oxidation at other positions) (Semino, 1998b).

 

Conjugation

(Hydroxy-) acids may be conjugated, e.g. glucuronidated or sulfated, and the resulting esters may subsequently be excreted via urine or bile. The conjugates may be cleaved in the gut, which opens the possibility of re-absorption of the more lipophilic alcohol moiety, distribution in the body etc. (entero-hepatic circulation).

Applicant's summary and conclusion

Conclusions:

Esters will be rapidly absorbed from the GI-tract either intact or already hydrolised into acid and alcohol. Biotransformation will be governed by hydrolysis as first step followed by oxidation reactions of the alcohol and subsequently the aldehyde and acid. In addition, oxidation at the alkyl fraim will occur. Conjugation is expected followed by urinary and biliary excretion.

Executive summary:

Esters will be rapidly absorbed from the GI-tract either intact or already hydrolised into acid and alcohol. Biotransformation will be governed by hydrolysis as first step followed by oxidation reactions of the alcohol and subsequently the aldehyde and acid. In addition, oxidation at the alkyl fraim will occur. Conjugation is expected followed by urinary and biliary excretion.