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basic toxicokinetics, other
Type of information:
Adequacy of study:
weight of evidence
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:
according to guideline
other: QSAR
Preliminary studies:
The compound gamma (-) hexalactone is a lactone compound. The compound exhibits a low oil-water partition coefficient with an experimental logP value of 0.3. In addition, -hexalactone is a food flavoring agent1. In this report, we initially applied ACD/ADME2 and DS/ADMET3 software packages, respectively, to estimate pharmacokinetic properties of -hexalactone. Finally, we predicted toxicokinetic (TK) properties of -hexalactone by combining the QSAR-derived data and published data of this compound.
Details on absorption:
Maximum passive absorption: 100%;
Transcellular route: 100%;
Paracellular route: 0%.
Human Jejunum Scale (pH 6.5): 10.03  10-4 cm/s;
Absorption rate: ka = 0.069 min-1.
Caco-2 (pH7.4, rpm 500) to predict cell membrane permeability using Caco-2 model;
Pe: 169  10-6 cm/s;
Transcellular route: 100%;
Paracellular route: 0%.
ACD/ADME-Absorption model calculations indicated that the compound gamma hexalactone could be absorbed in gastrointestinal tract (GI). Although this compound showed a low experimental logP value (0.3), it is a neutral organic compound with a high liposolubility, and the proper MW and molecular volume would make the compound pass the intestinal membrane easily. In addition, as the literature reported4, it was observed that patients with gastrointestinal disease had much higher amount of gamma hexalactone in their feces than asymptomatic volunteers. Therefore, it is possible for gamma hexalactone to be absorbed in GI.

DS/ADMET predicted ADMET_Absorption_Level is 0, suggesting -hexalactone would have a good absorption in jejunum. The result would be accordant with above ACD/ADME-Absorption predictions.
Details on distribution in tissues:
Plasma Protein Binding Ratio (PPB%): 56%, RI=0.49.
LogKaHSA: 4.01. The parameter represents the binding constant between compound and human serum albumin (HSA). RI=0.7.
Apparent volume of distribution, Vd = 1.1 L/Kg
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 ratio 8. ACD/ADME-Distribution calculations indicated that -hexalactone could bind with plasma protein in vivo with a very low binding ratio. Furthermore, the compound could bind mainly with lipoprotein but not with albumin since it’s not an organic acid .
Details on excretion:
As described above, the compound -hexalactone can be metabolized into 3-hydroxyhexanoic acid7. The metabolite with an increased water-solubility can be excreted by the urine11. In addition, literature reported that -hexalactone may also be excreted through feces in a little amount.4 Furthermore, as literature reported12, -hexalactone was monitored in human urine, indicating its excreted via urine too.
Details on metabolites:
Literature reported that -hexalactone may be hydrolyzed into the metabolite 3-hydroxyhexanoic acid under the effect of lactonase7.
Bioaccessibility (or Bioavailability) testing results:
Oral Bioavailability: F% < 30%. Reliability: 0.65.
ACD/ADME-Oral-Bioavailability model estimated that Gamma Hexalactone would exhibit a low oral bioavailability with a F% less than 30%. Although it was predicted that the compound can be absorbed into circulation system in vivo, this lactone can be hydrolyzed under the action of lactonase in blood, according to published data, leading to have a low blood concentration7. Therefore, -hexalactone would have a low oral bioavailability.


BBB permeability

LogPS: -1.6. This parameter represents the speed of passing BBB. The predicted value is larger, the rate is faster.   

LogBB: -0.15. 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 5, a compound with a LogBB value larger than 0.33 may possess high BBB permeability, and the LogBB value less than -1.0 indicates the compounds are difficult to pass the BBB. This compound was predicted to have a LogBB value close to -1.0, suggesting a low BBB permeability.

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

ACD/ADME-BBB model estimated that Gamma Hexalactone would have a medium BBB permeability to have a distribution in brain. Normally, it was acknowledged that a compound exhibiting the logP value more than 3 and M.W. less than 450 would be relatively easy to pass the BBB 6. Although g-hexalactone have a low LogP (0.3) unfavorable for BBB permeability, it is a neutral organic lactone with a high liposolubility. And also, its low molecular weight and volume will be favorable for it to pass the BBB. Furthermore, as a flavoring agent1, g-hexalactone must be in brain to have an activity on nervous system. Therefore, it is rational to predict this compound having a medium permeability.

P-gp Specificity

The ACD/ADME-P-gp Specificity model predicted g-hexalactone would not be an inhibitor or substrate of P-gp.

Normally, a compound with a molecular weight more than 400 and LogP higher than 3.00 may bind on P-gp to block its biological functions 10. Therefore, g-hexalactone with M.W. of 114.14 and logP of 0.3 would have a low chance to bind on P-gp for blocking its bio-functionality.

CYP450 Inhibitor

Non-Inhibitor of CYP450.

The ACD/ADME predicted that g-hexalactone would not be an inhibitor of CYP450. As an lactone organic substance, g-hexalactone may be metabolized via hydrolysis reaction catalyzed by hydrolase7. Hence, it would be rationally predicted that the compound would not be an inhibitor of CYP450.



BBB Level

DS/ADMET predicted the LogBB of 0.703 and Level of 0. Level 0 indicated g-hexalactone could pass the BBB easily, and the result would be congruent with above ACD/ADME-BBB predictions.


The calculated values: ADMET_EXT_CYP2D6: -7.245,ADMET_EXT_ CYP2D6#prediction:false, meaning the compound would not be an inhibitor of CYP2D6. The result would be congruent with ACD/ADME-P450 predictions.


DS/ADMET predicted ADMET_EXT_CYP2D6 to be -7.245,and ADMET_EXT _CYP2D6#prediction to be false. suggesting that the binding ratio of Gamma Hexalactone on plasma proteins is less than 90%. As like ACD/ADME-Distribution predictions, DS/ADMET also suggested that g-hexalactone would bind with plasma protein in a low level.

In summary, ACD/ADME and DS/ADMET, respectively, were applied to estimate PK data of the food flavoring agent gamma hexalactone. Based on the calculation data from these two different ADME prediction packages in combination with reported PK data of this compound, we predicted the TK properties of gamma hexalactone. As predicted, the compound could have a good absorption in gastrointestinal tract, buy have a low oral bioavailability of F% less than 30%. As a flavoring agent, the compound may pass the BBB to have a distribution in brain. Furthermore, it was predicted that it would bind on blood plasma protein with a low binding ratio less than 90%. As predicted, gamma hexalactone might not be an inhibitor or substrate of P-gp. Moreover, this compound would not be an inhibitor of CYP450. It can be hydrolyzed into the metabolite under the effect of lactonase, and the metabolite with increased water-solubility would be excreted by the urine. In addition, gamma hexalactone could also be directly excreted by urine and feces.

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