Triethyl O-acetylcitrate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Pharmacokinetics and Metabolism of Acetyl Triethyl Citrate, aWater-Soluble Plasticizer for Pharmaceutical Polymers in Rats

Author:

Kim H, Ji YS, Rehman SU, Choi MS, Gye MC, Yoo HH.

Year:

2019

Bibliographic source:

Pharmaceutics 11(4): 162; doi:10.3390/pharmaceutics11040162

Materials and methods

Objective of study:

metabolism

toxicokinetics

GLP compliance:

not specified

Remarks:

Data from Korea and not performed for REACH registration, GLP is not specified in the publication

Test material

Test material information

Constituent 1

Reference substance name:

Triethyl O-acetylcitrate

EC Number:

201-066-5

EC Name:

Triethyl O-acetylcitrate

Cas Number:

77-89-4

Molecular formula:

C14H22O8

IUPAC Name:

triethyl 2-acetoxypropane-1,2,3-tricarboxylate

Details on test material:

ATEC purchased from Sigma-Aldrich St. Louis, MO, USA

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Orient Bio (Seongnam, Korea)
- Age at study initiation: 8 weeks
- Weight at study initiation: approximately 250–290 g
- Housing: not reported
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 3
- Humidity (%): 55 +/- 15
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12
- Fasting period : 12 h

Administration / exposure

Route of administration:

other: oral and i.v.

Vehicle:

polyethylene glycol

Details on exposure:

30% poly-ethylene glycol (PEG) at a concentration of 10 mg/mL for intravenous (i.v.) administration and 500 mg/mL for oral (p.o.)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

i.v.

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day (nominal)

Remarks:

p.o.

No. of animals per sex per dose / concentration:

6

Control animals:

no

Details on dosing and sampling:

Blood samples (200 µL) were collected from the carotid artery in tubes containing 1 µL of heparin (5000 IU) and 5 µL of an esterase inhibitor, PMSF (1M). The collection time points were 1 min, 2 min, 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 10 h, and 24 h after the i.v. injection and 5 min, 15 min, 30 m, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 36 h after p.o. administration. The collected blood samples were
centrifuged at 10,000x g and 4 °C for 5 min, and the supernatant plasma was collected.

To determine the metabolic profile of ATEC, the rats were placed in metabolic cages for 5 days after oral dosing (500 mg/kg). Urine and feces were collected 10 h, 1 day, 2 day, 3 day, 4 day, and 4.3 day after oral administration.

Results and discussion

Main ADME results

Type:

clearance

Results:

Cl (L/h/kg): i.v. 125.1; p.o. 145.5

Toxicokinetic / pharmacokinetic studies

Details on excretion:

After i.v. administration, ATEC was rapidly eliminated with a terminal half-life of 0.03 and mean residence time of 0.03 h, whereas oral administration of ATEC resulted in 1.03 h of terminal half-life and a mean residence time of 6.56 h. Longer terminal half-life and residence time were observed after oral administration than intravenous injection.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

AUC: 78.1

Remarks:

i.v.

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

AUC: 529.6

Remarks:

p.o.

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

Cmax: 1219.6

Remarks:

i.v.

Toxicokinetic parameters 4

Test no.:

#2

Toxicokinetic parameters:

Cmax: 444.5

Remarks:

p.o.

Toxicokinetic parameters 5

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 0.03

Remarks:

i.v.

Toxicokinetic parameters 6

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 1.03

Remarks:

p.o.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The LC-QTOF MS analysis of plasma, urine and feces samples showed that ATEC was extensively metabolized and excreted mainly as metabolites rather than as the parent.
Acetyl diethyl citrate and diethyl citrate were the major metabolites of ATEC. Unchanged ATEC was mostly excreted within 24 h after the administration of the dose, but acetyl diethyl citrate and diethyl citrate were excreted up to 4 days after the dose.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

The absolute bioavailability (F) of ATEC was 14.8% (as calculated by the dose-corrected AUC p.o. divided by the AUC i.v.). This relatively low F value pointed to poor absorption of ATEC from the gastrointestinal tract, degradation of ATEC in the gut, and extensive first-pass effects. After i.v. administration,

Applicant's summary and conclusion

Conclusions:

The pharmacokinetic study showed that ATEC rapidly disappeared from plasma. The metabolite profiling data indicated that ATEC was extensively metabolized and excreted mainly as metabolites rather than as the parent form.