Ammonium carbonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable publication which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2002

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Study of the effects of infusion of ammonium bicarbonate on glutamine metabolism in ovine splanchnic tissues.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium hydrogencarbonate

EC Number:

213-911-5

EC Name:

Ammonium hydrogencarbonate

Cas Number:

1066-33-7

IUPAC Name:

ammonium hydrogen carbonate

Details on test material:

Purity: no data

Radiolabelling:

no

Test animals

Species:

sheep

Strain:

other: Suffolk cross wether

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 39 +/- 3.1 kg
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): 47 g grass pellets/0.75 kg bw/d as hourly portions
- Acclimation period: 3 weeks after surgery
- Other: prepared with vascular catheters in the aorta, mesenteric, portal and hepatic veins

Administration / exposure

Route of administration:

infusion

Vehicle:

water

Details on exposure:

TEST SCHEDULE
- For each animal, the experimental protocol involved 3 consecutive abomasal infusions of ammonium bicarbonate (23.4 μmol/kg, 365 μmol/min), an L-amino acid mixture at a rate of 730 μmol /min (46.8 μmol amino acid-N/kg) and water.
- L-glutamine solution (36 µM in sterile 0.15 M NaCl) was infused into the jugular catheter at a rate of 6 µmol/min the first 3 treatments.
On the fourth day the L-glutamine infusion was substituted by 100 ml 24 mM [5-15N]glutamine, which was infused at 6 µmol/min (15 g/h) for
6 h.

Duration and frequency of treatment / exposure:

Each infusion was for 4 days at a rate of 60 g/h, allowing at least 10 days between the ammonium bicarbonate and amino acid-N infusions.

Doses / concentrations

Remarks:

Doses / Concentrations:
- ammonium bicarbonate at a rate of 23.4 μmol/kg: 365 μmol/min
- L-amino acid mixture at a rate of 730 μmol /min: 46.8 μmol amino acid-N/kg

No. of animals per sex per dose / concentration:

Three animals were infused in the order: ammonium bicarbonate, water and amino acid while the other 3 received the reverse sequence.

Control animals:

yes

Details on study design:

Three animals were infused in the order AMM, CONT, AA while the other three received the reverse sequence (AA, CONT, AMM). Each infusion was for 4 d at a rate of 60 g/h, allowing at least 10 d between the AMM and AA treatments. The CONT infusion was allocated in the middle of the other two treatments to allow maximum time spacing between AA and AMM infusion, and was started at least 3 d after finishing the previous treatment.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling: Over 1 h intervals, between 2 and 6 h after [5- 15N]glutamine infusion

Results and discussion

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

- Blood flow across the whole gut or liver were unaffected by treatment.

- Both ammonium bicarbonate and amino acid-N infusions doubled the hepatic release of urea-N compared with water treatment.

- Ammonium acid infusion decreased arterial glutamine concentration by 26% and 23% compared with ammonium bicarbonate and water respectively. Despite this, whole-body glutamine flux was not affected by treatment. In contrast, ammonium bicarbonate infusion increased hepatic production by 40% compared with water. This provided a mechanism to ensure NH3 supply to the periphery was maintained within the normal low physiological levels. Hepatic glutamine utilisation tended to increase during amino acid infusion, probably to ensure equal inflows of N to the ornithine cycle. When NH3 supply exceeds the capacity of the ornithine cycle (periportal) then it is used as a substrate for glutamine synthesis (perivenous). Therefore, excess NH3 supply may lead to an increase in glutamine synthesis, while amino acid excess may increase hepatic glutamine use.

- Between 6 and 10% of NH3 absorbed across the digestive tract was derived from the amido-N of glutamine. Overall, splanchnic glutamine utilisation accounted for 45-70% of whole-body glutamine flux

Effects on on plasma ammonia and blood water urea concentration:

*p<0.005

		Ammonium bicarbonate	Water	Amino acids
NH3 concentration (µM)	Arterial	87	87	130
	Portal	489*	269	356*
	Hepatic	74	42	51
urea concentration (µM)	Arterial	8.61*	4.41	8.44*
	Portal	8.42*	4.31	8.32*
	Hepatic	8.81*	4.48	8.62*

Applicant's summary and conclusion

Conclusions:

In conclusion, splanchnic glutamine utilisation was shown to account for the majority of whole-body plasma glutamine flux, under conditions which simulated nutritional extremes in ruminant animals.

Executive summary:

This study investigates the effects of increased NH3 or amino acid supply on glutamine utilisation and production by the splanchnic tissues of fed sheep.

In conclusion, splanchnic glutamine utilisation was shown to account for the majority of whole-body plasma glutamine flux, under conditions which simulated nutritional extremes in ruminant animals. The PDV tissues had a lower demand for glutamine when amino acids were infused, indicative of sparing by other metabolites. Hepatic glutamine utilisation increased during both NH3 and amino acid infusion, while production increased by 40 %, compared with basal conditions, when ammonium bicarbonate was infused. This provided an effective strategy to prevent peripheral hyperammonaemia. Peripheral glutamine production contributed to the balance of

whole-body glutamine metabolism and varied with the form of nutrient supply.