Diheptyl succinate

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:

accepted calculation method

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Diheptyl succinate

EC Number:

239-996-9

EC Name:

Diheptyl succinate

Cas Number:

15872-89-6

Molecular formula:

C18H34O4

IUPAC Name:

1,4-diheptyl butanedioate

Test material form:

liquid

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Maximum passive absorption: 100%;
Transcellular route: 100%;
Paracellular route: 0%.
Permeability
Human Jejunum Scale (pH 6.5): 7.55E10-4 cm/s;
Absorption rate: ka = 0.052 min-1.
Caco-2 (pH7.4, rpm 500) to predict cell membrane permeability using Caco-2 model;
Pe: 55E10-6 cm/s;
Transcellular route: 100%;
Paracellular route: 0%.
The above ACD/ADME-calculated data suggested that Diheptyl Succinate would be absorbed rapidly in small intestine by passive absorption. In fact, the LogP of this compound is more than 5.1 and the water solubility is very low. Hence, it could pass the intestinal villi easily.

Details on distribution in tissues:

Plasma Protein Binding Ratio (PPB%): 97%, RI=0.48.
LogKaHSA: 5.40. The parameter represents the binding constant between compound and human serum albumin (HSA). RI=0.51.
The calculated data indicated that Diheptyl Succinate could bind with plasma proteins in vivo with high binding ratio. As known, the serum protein prefers weakly-acidic compound binding3. This compound is a hydrophobic compound, so it would bind with fat soluble proteins mainly but would not have good interaction with the serum albumin.

Details on excretion:

ACD/ADME doesn’t possess the ability of predicting the excretion properties of a compound. Diheptyl Succinate is similar with Dimethyl Succinate (Tanimoto:0.82), which was reported to be hydrolyzed of one ester under the effect of carboxylesterase to produce corresponding monoester compound6 excreted by urine. Therefore, it could be predicted that Diheptyl Succinate might also be hydrolyzed of one ester site to produce the compound 4-(heptyloxy)-4-oxobutanoic acid and Heptanol. Furthermore, it has been reported that Heptanol may be oxidized into heptylic acid in vivo excreted by the urine7. Hence, Diheptyl Succinate could be metabolized to the hydrophilic 4-(heptyloxy)-4-oxobutanoic acid and Heptylic acid in vivo and then excreted through urine.

Metabolite characterisation studies

Details on metabolites:

hydrogens connected with C1, C3, C4 and C6 could be oxidized into hydroxide. C2 and C5 could lose the corresponding alkane under the effect of hepatic microsomal enzyme.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Oral Bioavailability: F% < 30%. The predicted value means the oral bioavailability of the compound would be poor. Reliability: 0.769.
The ACD/ADME-predicted result suggested Diheptyl Succinate would display poor oral bioavailability. The poor water solubility would make this compound show the low oral bioavailability.