Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Toxikokinetic assessment
Adequacy of study:
key study
Study period:
March 2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Toxicokinetic assessment

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2015

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Toxicokinetic assessment, based on
- Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance
- ECB EU Technical Guidance Document on Risk Assessment, 2003
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Main ADME results
Type:
absorption
Results:
Oral route: 100%. Dermal route: 10 %. Inhalation route: 100 %

Any other information on results incl. tables

L-glutamine is a natural occurring amino acid and a natural constituent of peptides and proteins. Its content in most proteins is 3.9 % as an average (Römpp, 2015). Free L-glutamine often occurs in plant seedless during germination as well as in plants, animals, fungi and bacteria as a central metabolite in the metabolism of all organisms (Römpp, 2015; Belitz et al, 2007).

 

High contents of L-glutamine in the range of ca. 4 – 6.5 % are present in wheat, spelt flour, lentils, mungbeans, soybeans, peanuts, pork, mutton, beef and certain cheeses (DocMedicus, 2013). L-glutamine is a dietary source in these products. Small amounts of free L-glutamine are also found in vegetable juices (University of Maryland, 2009). However, it is not essential in humans.

 

L-glutamine belongs to the group of amino acids with uncharged, polar side chains.

 

Ammonia is quite toxic to animal tissue and thus much of free ammonia is converted to a nontoxic compound before export from the extrahepatic tissues into the blood. Excess ammonia in tissues is added to glutamate to form glutamine, a process catalyzed by glutamine synthetase. After transport in the bloodstream, the glutamine enters the liver and NH4+is liberated in mitochondria by the enzyme glutaminase. Glutamine synthesis scavenges ammonia more effectively than does the synthesis of glutamate, via glutamic acid dehydrogenase (GDH) (Young and Ajami, 2001).

 

The metabolic pathway of L-glutamine is linked with the metabolic pathways of L-arginine and L-proline. Thus, the net utilization or production of these amino acids is highly dependent on cell type and developmental stage (Lehninger et al, 2008).

 

 

Adsorption

L-glutamine is absorbed from the gastrointestinal tract. Ingested dietary protein is denatured in the stomach due to low pH. Denaturing and unfolding of the protein makes the chain susceptible to proteolysis. Up to 15% of dietary protein may be cleaved to peptides and amino acids by pepsins in the stomach. In the duodenum and small intestine digestion continues through hydrolytic enzymes (e.g. trypsin, chymotrypsins, elastase, carboxypeptidase). The resultant mixture of peptides and amino acids is then transported into the mucosal cells by specific carrier systems for amino acids and for di- and tripeptides.

 

The products of digestion are rapidly absorbed. Like other amino acids L-glutamine is absorbed from ileum and distal jejeunum.

 

 

Distribution

Absorbed peptides are further hydrolysed resulting in free amino acids which are secreted into the portal blood by specific carrier systems in the mucosal cell. Alternatively they are metabolised within the cell itself. Absorbed amino acids pass into the liver where a portion of the amino acids are used. The remainder pass through into the systemic circulation and are utilised by the peripheral tissue. L-glutamine is actively transported across the intestine from mucosa to serosal surface. The mechanism of absorption is that of the ion gradient. All L-amino acids are absorbed by Na+dependant, carrier mediated process. This transport is energy dependant by ATP. (All data from: Lehninger et al, 2008; Chatterjea and Shinde, 2012.)

 

Inhuman blood, glutamine is the most abundant freeamino acid, with a concentration of about 500–900 µM/l (Brosnan, 2003) and a median plasma concentration of 586 µM/l+84 µM/l (Cynober, 2002).

 

A number of hormones (e.g., thyroid hormone, catecholamines, and growth hormone) may affect plasma AA levels in diseases (Cynober et al., 1987). However, in the physiologic state, their influence is probably marginal.

 

 

Metabolism

There is no storage form for amino acids in animals and human except in the biologically active protein of the cells.

 

L-glutamine and L-glutamate may serve the same role in some metabolic functions due to their ready metabolic interconversion. The synthesis of glutamine is catalyzed by glutamine synthetase, a cytosolic activity that is found in many mammalian cells (Watford, 2000).

 

Glutamine is readily synthesised from glutamate and ammonium ions by the enzyme glutamine synthetase. This enzyme is present in liver and in many other body tissues. It has a low Kmfor ammonium, and works efficiently at non-toxic ammonium concentrations. The required energy comes from ATP. Glutamine supplies most of the nitrogen required for purine and pyrimidine biosynthesis, and for the manufacture of amino sugars. When necessary it can be degraded back to glutamate by the enzyme glutaminase (Lehninger, 2008).

 

 

Excretion

Body losses of amino acids are minimal because amino acids filtered by the kidneys are actively reabsorbed. This refers to normal doses of L-glutamine, too. Also cutaneous losses and losses via exhalation are negligible. Since there is no long term storage for amino acids in mammals, excess amino acids are degraded, mainly in the liver. Metabolism of amino acids involves removal of the amino group which is converted to urea and excreted in the urine. After removal of the amino group the rest of the acid is utilised as energy source or in anabolism of other endogenous substances.

 

L-glutamine is completely used by the organism after oral intake but rapidly converted or metabolised.

 

For risk assessment purposes oral absorption of L-glutamine is set at 100%.

 

L-glutamine is of low volatility due to a very low vapour pressure (0.00000253 Pa). From this and from the particle size it is not expected that L-glutamine reaches the nasopharyncheal region or subsequently the tracheobronchial or pulmonary region.

 

However, being a very hydrophilic substance with a molecular mass of only 146.15, any L-glutamine reaching the lungs might be absorbed through aqueous pores (ECHA, 2008). For risk assessment purposes, although it is unlikely that L-glutamine will be available to a high extent after inhalation via the lungs due to the low vapour pressure and high MMAD, the inhalation absorption of L-glutamine is set at 100%.

 

L-glutamine with high water solubility (41.3 g/L at 25°C and 35.7 g/L at 20°C) and the log P value very well below 0 (- 3.15) may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Therefore, 10% dermal absorption of L-glutamine is proposed for risk assessment purposes.

 

 

Citations:

Belitz H-D, Grosch W und Schieberle P. (2007): Lehrbuch der Lebensmittelchemie.6. Auflage. Springer-Verlag, Berlin and Heidelberg

 

J. Brosnan (2003): Interorgan amino acid transport and its regulation. J. Nutr. 133 (6 Suppl. 1), 2068S – 2072S

 

Chatterjea M and Shinde R (2012): Textbook of Medical Biochemistry. Jaypee Brothers Medical Publishers, New Delhi

 

Cynober L, Coudray-Lucas C, Ziegler F, et al. (1987): Métabolisme azote´ chez le sujet sain. Nutr Clin Metabol; 3:87

 

Cynober L (2002): Plasma Amino Acid Levels With a Note on Membrane Transport: Characteristics, Regulation, and Metabolic Significance.Nutrition 18 (9), 761-766

 

DocMedicus (2013):Glutamingehalt von Lebensmitteln.Deutsche Gesellschaft für Nährstoffmedizin und Prävention

 

ECHA (2008): Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance

 

Lehninger A, Nelson D, Cox M (2008), Principles of Biochemistry (5th ed.), New York: W. H. Freeman

 

Römpp (2015): Römpp Online.Georg Thieme Verlag

 

University of Maryland (2009):Medical Reference Guide of theUniversity of Maryland Medical Center

 

Watford, M (2000): Glutamine and Glutamate Metabolism across the Liver Sinusoid. J. Nutr. 130: 983S–987S

 

Young, V and Ajami, A (2001): Glutamine metabolism: Nutritional and clinical significance. J. Nutr. 131 (9), 2449S – 2459S

 

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: The absorption factors for risk assessment purposes have been set as follows: absorption oral 100%, absorption dermal 10% and absorption inhalation 100%
For risk assessment purposes:
Absorption oral: 100%,
Absorption dermal: 10%
Absorption inhalation: 100%