Dihydro-5-octylfuran-2(3H)-one

Endpoint summary

Link to relevant study record(s)

Reference

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

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

other: QSAR

Preliminary studies:

5-octyldihydrofuran-2(3H)-one is to be a lactone compound. It almost couldn’t dissolve into water with a water solubility of 0.06 g/L. Moreover, its experimental oil-water partition coefficient LogP value is 2.7, meaning a normal fat-soluble level. We predicted toxicokinetic (TK) properties of 5-octyldihydrofuran-2(3H)-one by taking advantage of both ACD/ADME1 and DS/ADMET software packages2, respectively, in combination with literature reports of similar compound’s pharmacokinetics.

Details on absorption:

ACD/ADME
Maximum passive absorption: 100%;
Transcellular route: 100%;
Paracellular route: 0%.
Permeability
Human Jejunum Scale (pH 6.5):8.76´10-4cm/s;
Absorption rate:ka=0.060min-1.
Caco-2 (pH7.4, rpm 500)to predict cell membrane permeability using Caco-2 model;
Pe:238´10-6cm/s;
Transcellular route: 100 %;
Paracellular route: 0 %.
The ACD/ADME-HIA 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, proper lipid solubility and low molecular weight of 5-octyldihydrofuran-2(3H)-one would make this compound pass the intestinal easily. Furthermore, it has been reported that the similar compound 1,4-butyrolactone (Figure 2, similarity coefficient: 0.79) could be absorbed in rat’s gastrointestinal tract. Hence, it would be rational to predict 5-octyldihydrofuran-2(3H)-one to be absorbed in gastrointestinal tract rapidly.

DS/ADMET
DS/ADMET predicted ADMET_AlogP98 of 3.914, level, 0. Level 0 represented 5-octyldihydrofuran-2(3H)-one could be absorbed in jejunum, which was accordant with above ACD/ADME-Absorption prediction.

Details on distribution in tissues:

ACD/ADME
Plasma Protein Binding Ratio (PPB%): 89 %, RI=0.54.
LogKaHSA: 4.61. The parameter represents the binding constant between compound and human serum albumin (HSA). RI=0.34.
Generally, the binding rate more than 95% means a high binding ratio on plasma protein, 90% to 95% for a moderate binding ratio, and less than 90% for a low binding ratio. ACD/ADME-distribution model calculated data indicated that 5-octyldihydrofuran-2(3H)-one may bind with plasma protein in vivo with a low binding ratio less than 90%7. In the meantime, this compound would not bind tightly with the human albumin, since serum protein prefers a weakly-acidic compound8.

Details on excretion:

ACD/ADME
According to above ACD/ADME-metabolism predictions, 5-octyldihydrofuran-2(3H)-one could be metabolized into 4-hydroxydodecanoic acid under hydrolysis or other hydroxylic compounds under hydroxylation, and both 4-hydroxydodecanoic acid and hydroxylic compound with improved water solubility may be excreted via urine. Furthermore, the formed 4-hydroxydodecanoic acid may be transferred to CO2, breathed out via respiratory system, under decarboxylation.

Details on metabolites:

ACD/ADME
The predicted data from ACD/ADME indicated that the lactone part of this compound could be hydrolyzed to be a r-hydroxyl acid. Aliphatic carbons, typically C2, C3, C4, C5, C6, and C7, could be hydroxylated with highly predicted reaction probability and score to get corresponding hydroxyl compounds. As reported10, above-mentioned similar compound 1,4-butyrolactone was actually metabolized to get 4-hydroxybutanoic acid in vivo, and 4-hydroxybutanoic acid was further transferred to form CO2, exhaled via respiratory system, under a decarboxylic reaction. Based on above discussion, it would be rational to predict 5-octyldihydrofuran-2(3H)-one hydrolyzed to generate 4-hydroxydodecanoic acid, further forming CO2, or hydroxylated at C2, C3, C4, C5, C6, or C7 to get corresponding hydroxyl compounds.

Bioaccessibility (or Bioavailability) testing results:

ACD/ADME
Oral bioavailability: < 30%. Reliability: 0.650.
ACD/ADME predicted that 5-octyldihydrofuran-2(3H)-one would have a low level of oral bioavailability with a relatively-high reliability. The very low water solubility and relatively low LogP value may make 5-octyldihydrofuran-2(3H)-one have a low oral bioavailability.

ACD/ADME

BBB permeability

LogPS: -1.2. This parameter represents the speed of passing BBB. The predicted value is larger, the rate is faster.  

LogBB: 0.01. 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.5-octyldihydrofuran-2(3H)-onewas predicted to have a LogBB value less than 0.33, suggesting a moderate BBB permeability.

Log (PS*fu, brain): -2.1. 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 might pass the BBB moderately. Actually, it has been reported that a compound possessing a LogP value between 3 and 5 would be relatively easy to pass the BBB. Although5-octyldihydrofuran-2(3H)-one has a very low water solubility of 0.06g/L, itsLogP value of 2.7 might have it to pass the BBB without an easy way.

P-gp Specificity

P-gp Inhibitors: Non inhibitor;

P-gp Substrate: Non substrate;

Reliability: high.

The low molecular weight, less than 250, of5-octyldihydrofuran-2(3H)-onemay 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 also could be metabolized by the enzyme. Hence, the predicted compound 5-octyldihydrofuran-2(3H)-onemay not be an inhibitor of enzyme neither, and could be metabolized by corresponding enzyme.

DS/ADMET

BBB Level

DS/ADMET predicted the LogBB of 0.641, Level 1, indicating5-octyldihydrofuran-2(3H)-onecould pass the BBB moderately. The result was congruent with above ACD/ADME-BBB predictions.

ADMET_CYP2D6

ADMET_CYP2D6_Probability was predicted to be0.069, Level 0. Level 0meant5-octyldihydrofuran-2(3H)-one would not be an inhibitor of CYP2D6, which was consistent with ACD/ADME-P450predictions.

ADMET_PPB_Level

DS/ADMET predicted ADMET_AlogP98 of 3.914 and level 0, suggesting that5-octyldihydrofuran-2(3H)-one’sbinding ratio on plasma proteins less than 90%. As ACD/ADME-Distributionpredictions, DS/ADMET also suggested that5-octyldihydrofuran-2(3H)-onecould bind with plasma protein in a relatively low level.

Conclusions:

In summary, both ACD/ADME and DS/ADMET were respectively applied to predict TK properties of 5-octyldihydrofuran-2(3H)-one. According to estimated data from two different software packages in combination with literature-reported data of the similar compound, it was predicted that 5-octyldihydrofuran-2(3H)-one could be absorbed in small intestine. It could pass the BBB moderately. The compound would have a low level of oral bioavailability less than 30%. Furthermore, 5-octyldihydrofuran-2(3H)-one could bind with plasma protein in blood with a low binding ratio less than 90%, and it would not be an inhibitor or substrate of P-gp. Moreover, it was also predicted that the compound would not be an inhibitor of CYP450. 5-octyldihydrofuran-2(3H)-one might be metabolized into 4-hydroxydodecanoic acid or other hydroxyl compounds, which might be excreted via urine, with improved water solubility. The formed 4-hydroxydodecanoic acid might be further transferred into CO2, exhaled in respiratory system.