Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Objective of study:
absorption
bioaccessibility (or bioavailability)
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
according to guideline
Guideline:
other: ACD/ADME and Discovery Studio
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Diethyl ethylphosphonate
EC Number:
201-111-9
EC Name:
Diethyl ethylphosphonate
Cas Number:
78-38-6
Molecular formula:
C6H15O3P
IUPAC Name:
diethyl ethylphosphonate
Test material form:
liquid

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Maximum passive absorption: 100%;
Transcellular route: 100%;
Paracellular route: 0%.
Human Jejunum Scale (pH 6.5):9.63*10-4 cm/s;
Absorption rate: ka = 0.066 min-1.
Caco-2 (pH7.4, rpm 500)to predict cell membrane permeability using Caco-2 model;
Pe: 173*10-6 cm/s;
Transcellular route: 100%;
Paracellular route: 0%.
The ACD/ADME calculated data indicated that diethyl ethylphosphonate 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. Because of its small molecular size and low molecular weight (M.W.=166.16), it would make this compound pass the small intestine easily. Furthermore, this compound could be miscible with water in any ratio, and possesses appropriate LogP value. All of the corresponding physicochemical properties could make this compound pass the small intestine. It has been reported that the highly similar compound dimethyl methylphosphonate (Tanimoto:0.91) could be absorbed rapidly by oral administration. Hence, the predicted compound exhibits high similarity with dimethyl methylphosphonate (Tanimoto: 0.91), and it also could be absorbed rapidly.
Details on distribution in tissues:
Plasma Protein Binding Ratio(PPB%): 32%, RI=0.43.
LogKaHSA: 3.20. The parameter represents the binding constant between compound and human serum albumin (HSA). RI=0.20.
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 diethyl ethylphosphonate may bind with plasma protein in vivo with a low binding rate 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:
The ACD/ADME predications indicated that C1 and C2 could be dealkylated under the effect of enzyme. Moreover, C3 and C4 could be oxidized into hydroxyl. In fact, it was reported that dimethyl dethylphosphonate could be dealkylated to form dimethylphosphonate, then excreted by the urine. Therefore, diethyl ethylphosphonate possessing high similarity with dimethyl methylphosphonate also could be dealkylated and form diethylphosphonate.
According to above ACD/ADME predictions of metabolism of diethyl ethylphosphonate, it could be metabolized into dealkylated compounds, like diethylphosphonate, and excreted by the urine.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The ACD/ADME predications indicated that C1 and C2 could be dealkylated under the effect of enzyme. Moreover, C3 and C4 could be oxidized into hydroxyl. In fact, it was reported that dimethyl dethylphosphonate could be dealkylated to form dimethylphosphonate, then excreted by the urine

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
Oral Bioavailability: > 70%.Reliability: 0.756.
ACD/ADME predications indicated that diethyl ethylphosphonate would have a goodoral bioavailability with a high reliability. This compound displaying excellent water solubility and other corresponding physicochemical properties, like small size and moderate LogP value, may make diethyl ethylphosphonate have a good oral bioavailability.

Any other information on results incl. tables

LogPS: -1.7. This parameterrepresents the speed of passing BBB. The predicted value is larger, the rate is faster. 

LogBB: 0.08. 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 0.33may 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): -1.9. This parameter represents blood-brain equilibrium constant. The predicted data indicated this compound could distribute into brain with a moderate amount.

Based on ACD/ADME-calculated data indicated that diethyl ethylphosphonate could pass the BBB moderately. Its moderate LogP value would make the compound not pass the BBB easily. On the other hand, its low molecular weight and low molecular volume would favorBBBpermeability. Therefore, it would be rational to predict diethyl ethylphosphonate passing the BBB moderately.

P-gp Inhibitors: Non inhibitor;

P-gp Substrate: Non substrate;

Reliability: high.

The low molecular weight,less than 250, ofdiethyl ethylphosphonate, may lead this compound unfavorably binding on P-gp to be an inhibitor or substrate of P-gp.

Non-Inhibitor of CYP450

It has been reported that dimethyl methylphosphonate could be oxidized by hepatic microsomal enzyme. It would be rational to predict diethyl ethylphosphonate metabolized by corresponding enzyme, since it possesses high molecular similarity with dimethyl methylphosphonate (Tonimoto: 0.91).

DS/ADMET predicted ADMET_AlogP98 of0.914 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 that predicted compound could 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 diethyl ethylphosphonate. According to the calculated data from two different software packages in combination with reported experimental data of some similar compounds, it was predicted diethyl ethylphosphonate could be absorbed in small intestine and it could pass the BBB moderately. This compound would have a high level of oral bioavailability. Furthermore, it would not bind with blood plasma protein ata high rate and would not be neither an inhibitor or substrate of P-gp nor an inhibitor of CYP450. Moreover, diethyl ethylphosphonate might be metabolized by corresponding enzymes into dealkylated compounds, like diethylphosphonate, then excreted by the urine.