Sodium formate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

Toxicokinetic modeling of dose-dependent formate elimination in rats: in vivo-in vitro correlations using the perfused rat liver.

Author:

Damian P and Raabe OG

Year:

2001

Bibliographic source:

Toxicol Appl Pharmacol 139, 22-32.

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Toxicokinetic modeling: in vivo - in vitro correlations using the perfused rat liver. Development of a toxicokinetic model using data from perfused rat liver experiments, and model evaluation in vivo.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Sodium formate

EC Number:

205-488-0

EC Name:

Sodium formate

Cas Number:

141-53-7

Molecular formula:

CHO2Na

IUPAC Name:

sodium formate

Details on test material:

- Name of test material (as cited in study report): sodium formate

Specific details on test material used for the study:

- Name of test material (as cited in study report): sodium formate

Radiolabelling:

no

Test animals

Species:

rat

Administration / exposure

Route of administration:

other: C34-001:perfusate (perfused liver experiments) and i.v. (in-vivo experiments)

Vehicle:

water

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2 other: mM

Remarks:

in vitro test; in terms of sodium formate

Doses / concentrations 2

Dose / conc.:

4 other: mM

Remarks:

in vitro test; in terms of sodium formate

Doses / concentrations 3

Dose / conc.:

8 other: mM

Remarks:

in vitro test; in terms of sodium formate

Doses / concentrations 4

Dose / conc.:

12 other: mM

Remarks:

in vitro test; in terms of sodium formate

Doses / concentrations 5

Dose / conc.:

41 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

Doses / concentrations 6

Dose / conc.:

164 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

Doses / concentrations 7

Dose / conc.:

328 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

Doses / concentrations 8

Dose / conc.:

492 mg/kg bw (total dose)

Remarks:

in vivo test; in terms of sodium formate

No. of animals per sex per dose / concentration:

Males: 92

Control animals:

yes

Details on study design:

- Dose selection rationale: dose levels were estimated from target plasma concentration assuming a rapid mixing after intravenous injection and a total body water volume of 60% of the body weight.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (in vivo)
- Tissues and body fluids sampled: urine, blood
- Time and frequency of sampling:
Blood: at 15 min before dosing and 5, 10, 15, 20, 30, 40, 50 min and 1, 1.25, 1.5, 1.75., 2, 2.25, 2.5, 2.75, and 3 hr after dosing.
Urine: 20 min and 3, 8, 12, 20, and 28 hr after dosing.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not applicable (i.v. injection)

Details on distribution in tissues:

not examined

Details on excretion:

Urinary excretion at 3 hours after dosing accounted for 8/34/45/55% at plasma target levels of 1/4/8/12 mM.

Any other information on results incl. tables

1) Perfused liver
i) experiment without liver: formate was not lost from the perfusion system without liver.
ii) experiments with liver: elimination of formate was dose-dependent. Saturation of metabolic elimination was

evident beginning at 4 mM. Formate elimination was virtually linear when plotted on a linear scale. Elimination rates calculated from the slope of the elimination curves for the 2, 4, 8, and 12 mmM dose were 7.1, 16.0, 22.8, and 26.4 µmol/hour/g liver, respectively. Good agreement between the model prediction and the measured perfusate concentrations were obtained (correlation coefficient r²= 0.9996). 

Table 1: statistical results for the perfused liver model:  

Maximal rate	Vmax  = 0.0100 mmol/min
Michaelis constant	KM    = 1.324 mM
endogenous liver formate production	KO    = 0.002 mmol/min

2) In-vivo studies

Elimination of formate from plasma was very rapid at all dose levels. Endogenous levels (approx. 0.06 mM) were

reached at approx. 3 hours.  The plasma curves showed nonlinearities in the elimination of formate across doses in

the log concentration-time plot.

Urinary excretion was initially very rapid. The cumulative excretion had reached the steady state condition of the endogenous formate excretion 

3 h after dosing.

Table 2: Urinary formate excretion in the rat
 

Target concentration  (mM)	Dose (mg/kg bw)	Total dose (mmol)	Urinary excretion (% of dose by 3 hours)
			Experiment (mean, n=4)	Model prediction
1	41	0.21	19	8
4	164	0.84	35.1	34
8	328	1.68	42.7	45
12	492	2.52	48.3	55

3) The toxicokinetic model 
The toxicokinetic model predicted both the rapid initial excretion and the steady state concentrations in good

agreement with the in-vivo  experiments, indicating a good fit of the model. Predictions for the in-vivo experiments (tabulated below) were in good agreement with the perfusion data.

Table 3: Model predictions for the in vivo situation

Maximal rate	Vmax  = 0.016 mmol/min
Michaelis constant	KM    = 1.84 mM
endogenous liver formate production	KO    = 0.00052 mmol/min

 

The simulated proportions of formate excretion via hepatic metabolism and urinary excretion indicate that the liver can account for virtually all formate metabolism in vivo:
 

Dose level (mM)	% of dose elimiminated by 3 hours)
	Hepatic metabolism	Urinary excretion
1	92	8
4	66	34
8	55	45
12	45	55

 

Regarding the toxicological behavior: Elimination follows Michaelis-Menten kinetics. Hepatic metabolism  prevails at plasma levels up to 1 mM. Urinary elimination

 accounts for up  to 50% at high plasma levels. No accumulation to be considereed in the rat in-vivo.

Applicant's summary and conclusion

Conclusions:

Data obtained in rat perfused liver experiments indicated that formate is rapidly eliminated from the perfusate at all tested perfusate concentrations of 2, 4, 8, and 12 mM. The elimination was dose dependent, and metabolic saturation was seen at 4 mM and above.
A 2-compartment toxicokinetic model was developed and used to predict the elimination of formate. The model prediction fitted well with the
measured values and allowed to calculate the Michaelis-Menten constants of the metabolic reactions.
In-vivo experiments confirmed both the model prediction and the results of the liver perfusions.
Key findings of the presented studies include:
i) The rat perfused liver model and the toxicokinetic model were both suitable to model the in-vivo situation following low and high formate doses.
ii) Elimination of formate in vivo is saturable and follows Michaelis-Menten kinetics. Predicted constants are Vmax=0.016 mmol/min and
KM=1.84 mM.
iii) The endogenous formate generation in liver is calculated to be KO=0.00052 mmol/min.
iv) Hepatic metabolism of formate prevails (92% of elimination) over urinary excretion (8%) at the low dose (1 mM). At physiological plasma levels
(approx. 0.06 mM) hepatic metabolism is considered to play the major role for elimination. At higher plasma levels the urinary excretion
accounted for op to approx. 50% of the elimination.
v) In the in-vivo experiments, plasma levels of up to 12 mM returned to normal (0.06 mM) within 3 hours after dosing.
Thus, there was no indication of accumulation of formate in the rat.