Octan-4-olide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

other: QSAR

Test material

Test material information

Constituent 1

Reference substance name:

Octan-4-olide

EC Number:

203-208-1

EC Name:

Octan-4-olide

Cas Number:

104-50-7

Molecular formula:

C8H14O2

IUPAC Name:

octan-4-olide

Results and discussion

Preliminary studies:

5-butyldihydrofuran-2(3H)-one is a lactone compound. It could be dissolved into water slightly with a water solubility of 5.6 g/L. Moreover, its experimental oil-water partition coefficient LogP value is 1.5, meaning not high fat solubility. We predicted TK properties of 5-butyldihydrofuran-2(3H)-one using both ACD/ADME1 and DS/ADMET software packages2, respectively.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

ACD/ADME
Absorption
Maximum passive absorption: 100%;
Transcellular route: 100%;
Paracellular route: 0%.
Permeability
Human Jejunum Scale (pH 6.5): 9.7210-4 cm/s;
Absorption rate: ka = 0.067 min-1.
Caco-2 (pH7.4, rpm 500) to predict cell membrane permeability using Caco-2 model;
Pe: 20610-6 cm/s;
Transcellular route: 100 %;
Paracellular route: 0 %.
The ACD/ADME calculated data indicated that the predicted compound could be absorbed in small intestine by passive absorption rapidly. In fact, when the concentration in gastrointestinal tract is more than in blood, the compound would be absorbed by passive absorption mainly. The small molecular size and low molecular weight would make this compound pass the intestinal easily. Actually, it has been reported that the similar compound 1,4-Butyrolactone could be absorbed in rat’s gastrointestinal tract3. Hence, 5-butyldihydrofuran-2(3H)-one also might be absorbed in gastrointestinal tract rapidly.

DS/ADMET
ADMET_Absoption_Level
DS/ADMET predicted the ADMET_AlogP98 of 2.09 and level of 0. Level 0 represented 5-butyldihydrofuran-2(3H)-one could be absorbed in jejunum, which was accordant with above ACD/ADME-Absorption predictions.

Details on distribution in tissues:

ACD/ADME
Distribution
Plasma Protein Binding Ratio (PPB%): 67 %, RI=0.54.
LogKaHSA: 3.39. The parameter represents the binding constant between compound and human serum albumin (HSA). RI=0.28.
Normally, the binding rate more than 95% means a high binding rate on plasma protein, 90% to 95% for a moderate binding rate, and less than 90% for a low binding rate. ACD/ADME-calculated data indicated that 5-butyldihydrofuran-2(3H)-one may bind with plasma protein in vivo with a low binding ratio less than 90%. In the meantime, this compound would not bind tightly with the human albumin, since serum protein prefers a weakly-acidic compound.

Details on excretion:

ACD/ADME
Excretion
According to above ACD/ADME-metabolism predictions, 5-butyldihydrofuran-2(3H)-one could be metabolized to -hydroxyoctanoic acid in hydrolysis reaction or other hydroxylic compounds in hydroxylation reaction, and both 4-hydroxydodecanoic acid and hydroxylic compounds may have improved water solubility to be excreted via urine. Furthermore, the formed 4-hydroxydodecanoic acid may be decarboxylated to CO2, breathed out through respiratory system.

Metabolite characterisation studies

Details on metabolites:

ACD/ADME
Metabolism
The predicted data from ACD/ADME indicated that the lactone part of 5-butyldihydrofuran-2(3H)-one might be hydrolyzed to produce 4-hydroxyoctanoic acid. All additional Aliphatic carbons were predicted to conduct hydroxylated reaction to produce corresponding hydroxyl compounds with high reaction probability and prediction reliability. Above mentioned similar compound 1,4-Butyrolactone was reported to be metabolized to 4-hydroxybutanoic acid, and 4-hydroxybutanoic acid may be further transferred into CO2, eliminated from the body, under the affection of decarboxylase in vivo 7. Therefore, it was also suggested that the formed -hydroxyoctanoic acid may be changed to CO2 via decarboxylation reaction.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

ACD/ADME
Oral Bioavailability (F%)
Oral Bioavailability: < 30%. Reliability: 0.650.
ACD/ADME predications indicated that 5-butyldihydrofuran-2(3H)-one would have a low level of oral bioavailability with a high prediction reliability. This compound displaying slight water solubility and other corresponding physicochemical properties, like relatively low LogP value, may make 5-butyldihydrofuran-2(3H)-one have a low oral bioavailability.

Any other information on results incl. tables

ACD/ADME

BBB

LogPS: -1.4. This parameter represents the speed of passing BBB. The predicted value is larger, the rate is faster.  

LogBB: -0.07. This parameter represents the ratio of compound between brain and blood under the steady state conditions. The predicted value is greater, the amount in brain is more. As reported, a compound with a LogBB value larger than 0.33 may possess high BBB permeability, and the LogBB value less than -0.1 indicates the compounds are difficult to pass the BBB.This compoundwas predicted to have a  LogBB value less than 0.33, suggesting a moderate BBB permeability.

Log (PS*fu, brain): -1.8. This parameter represents blood-brain equilibrium constant. The predicted data indicated this compound could distribute into brain with a large amount.

ACD/ADME-predicted data indicated that this compound passed the BBB moderately. In fact, it has been reported that a compound with LogP value between 3 and 5 would be relatively easy to pass the BBB. The LogP value of predicted compound (1.5) would make it not pass the BBB easily.

P-gp Specificity

P-gp Inhibitors: Non inhibitor;

P-gp Substrate: Non substrate;

Reliability: high.

The low molecular weight, less than 250, of5-butyldihydrofuran-2(3H)-one, may lead this compound unfavorably binding on P-gp to be an inhibitor or substrate of P-gp.

CYP450 Inhibitor

Non-Inhibitor of CYP450

It has been reported that 1,4-Butyrolactone (Figure 2) also could be metabolized by the enzyme. Hence, the predicted compound5-butyldihydrofuran-2(3H)-one may not be an inhibitor of enzyme neither, and could be metabolized by corresponding enzyme.

DS/ADMET

BBB Level

DS/ADMET predicted the LogBB of 0.077 and Level of 1. Level 1 indicated5-butyldihydrofuran-2(3H)-onecould pass the BBB moderately, and the results was congruent with above ACD/ADME-BBB predictions.

ADMET_CYP2D6

The calculated ADMET_CYP2D6_Probability:0.059, Level：0.It meant5-butyldihydrofuran-2(3H)-onewould not be an inhibitor of CYP2D6, which was congruent with ACD/ADME-P450predictions.

ADMET_PPB_Level

DS/ADMET predicted ADMET_AlogP98 of 2.09 and level of 0. It suggested that the binding ratio on plasma proteins is less than 90%. ADMET_AlogP98 <4.0 represented the binding ratio would be less than 90%. As like ACD/ADME-Distributionpredictions, DS/ADMET also suggested that5-butyldihydrofuran-2(3H)-onecould bind with plasma protein in a low level.

Applicant's summary and conclusion

Conclusions:

In summary, both ACD/ADME and DS/ADMET, respectively, were applied to predict TK properties of 5-butyldihydrofuran-2(3H)-one. According to the calculated data from two different software packages in combination with reported experimental data of similar compound 5-butyldihydrofuran-2(3H)-one, 5-butyldihydrofuran-2(3H)-one was predicted to be absorbed in small intestine. It could pass the BBB moderately. This compound would have a low level of oral bioavailability with an F% less than 30%. Furthermore, it could bind with plasma protein in blood with a ratio less than 90%. The compound was predicted to be non-inhibitor or non-substrate of P-gp. 5-butyldihydrofuran-2(3H)-one would not be an inhibitor of CYP450 neither. It might be metabolized into -hydroxyoctanoic acid by esterolysis reaction or other hydroxyl compounds via hydroxylation. The formed γ-hydroxyoctanoic acid or hydroxyl compounds might be excreted via urine with improved water solubility. The formed 4-hydroxyoctanoic acid might be further transferred into CO2, exhaled through respiratory system.