Drug compounds have been modified to include stable heavy isotopes of hydrogen, carbon, and other elements. These isotopes are mostly utilized as quantitative tracers during the drug development process. 1].

Absorption, Distribution and Excretion
Absorption is highly efficient, occurring via active transport mechanisms. The time to peak concentration (Tmax) after a single dose is 30 minutes. Absorption kinetics after multiple doses have not been determined. Excretion is primarily via metabolism. L-glutamine is filtered by the glomerulus but is almost entirely reabsorbed by the renal tubules. The volume of distribution after intravenous bolus administration is 200 mL/kg. In three subjects, the estimated volume of distribution after intravenous bolus administration was approximately 200 mL/kg. In six subjects, the mean peak plasma glutamine concentration after a single oral dose of 0.1 g/kg was 1028 μM (or 150 mcg/mL), occurring approximately 30 minutes after administration. Pharmacokinetics after multiple oral doses have not been fully characterized. Metabolism is the primary pathway for glutamine clearance. Although glutamine is cleared by glomerular filtration, it is almost entirely reabsorbed by the renal tubules.

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Metabolism/Metabolites
Exogenous L-glutamine may follow the same metabolic pathway as endogenous L-glutamine, participating in the synthesis of glutamate, proteins, nucleotides, and amino acid sugars.
Glutamine plays an important role in nitrogen homeostasis and intestinal substrate supply. Studies have shown that glutamine can become a precursor of arginine via the entero-renal pathway (involving inter-organ transport of citrulline). However, the importance of intestinal glutamine metabolism for the synthesis of endogenous arginine in humans remains unclear. This study aimed to investigate the process of glutamine conversion to citrulline in the intestine and the influence of the liver on visceral citrulline metabolism in humans. Eight patients undergoing upper gastrointestinal surgery received a continuous intravenous infusion of pre-prepared [2-(15)N]glutamine and [ureido-(13)C-(2)H(2)]citrulline. Arterial, portal venous, and hepatic venous blood samples were collected, and portal venous and hepatic venous blood flow were measured. Amino acid uptake (clearance), production, and net balance in various organs, as well as the presence of amino acids in systemic plasma, were calculated using established methods. The rate of glutamine consumption in the intestine depends on the glutamine supply. Approximately 13% of glutamine taken up by the intestine is converted to citrulline. Quantitative analysis showed that glutamine is the only important precursor for citrulline release from the intestine. Both glutamine and citrulline are consumed and produced by the liver, but the net hepatic flux of both amino acids was not significantly different from zero. Plasma glutamine is a precursor for 80% of plasma citrulline, while plasma citrulline is a precursor for 10% of plasma arginine. In summary, glutamine is an important precursor for the synthesis of arginine from citrulline in the human intestine. Endogenous glutamine participates in various metabolic activities, including the production of glutamate and the synthesis of proteins, nucleotides, and amino sugars. Exogenous glutamine is expected to undergo similar metabolic processes. The elimination half-life for intestinal cells and the liver is 1 hour. In three subjects, the terminal half-life of glutamine was approximately 1 hour after intravenous bolus injection.

Toxicity Summary
L-glutamine supplementation may have immunomodulatory effects, which can be explained in several ways. L-glutamine appears to play a crucial role in protecting the integrity of the gastrointestinal tract, particularly the large intestine. In a catabolic state, the integrity of the intestinal mucosa can be compromised, leading to increased intestinal permeability and the translocation of Gram-negative bacteria from the large intestine into the body. The demand for L-glutamine from the gut and cells such as lymphocytes appears to far exceed the supply from skeletal muscle (the primary storage tissue for L-glutamine). L-glutamine is the preferred respiratory fuel for intestinal cells, colon cells, and lymphocytes. Therefore, L-glutamine supplementation in these conditions may have multiple effects. First, it may reverse the catabolic state by protecting L-glutamine in skeletal muscle. It may also inhibit the translocation of Gram-negative bacteria from the large intestine. L-glutamine helps maintain secretory IgA, whose primary function is to prevent bacterial adhesion to mucosal cells. L-glutamine appears to be essential for supporting mitogen-stimulated lymphocyte proliferation and the production of interleukin-2 (IL-2) and interferon-γ (IFN-γ). It is also necessary for maintaining lymphokine-activated killer cells (LAK). L-glutamine can enhance phagocytosis by neutrophils and monocytes. It can lead to increased glutathione synthesis in the gut, which may play a role in maintaining intestinal mucosal integrity by mitigating oxidative stress. However, the exact mechanism by which L-glutamine supplementation may exert immunomodulatory effects is unclear. The primary action of L-glutamine likely occurs at the intestinal level. Perhaps intestinal L-glutamine acts directly on gut-associated lymphoid tissue and stimulates overall immune function through this mechanism, without passing through areas outside the visceral bed.

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Hepatotoxicity
In clinical trials of L-glutamine in patients with sickle cell disease, elevated serum transaminases and clinically significant liver injury were not reported. Jaundice is common in patients with sickle cell disease, primarily due to elevated serum indirect bilirubin levels caused by chronic hemolysis.
Patients with sickle cell disease may also experience abnormal fluctuations in liver function due to complications such as gallstones (caused by chronic hemolysis), viral hepatitis and iron overload (caused by blood transfusions), congestive liver disease (caused by pulmonary hypertension), and venous occlusive crisis involving the liver (which may be accompanied by elevated serum transaminases and liver dysfunction). In pre-registration trials of L-glutamine, no adverse liver events were reported, and the incidence of serious adverse events was not significantly different between the active drug group and the placebo group. L-glutamine is a normal component of almost all tissues and is unlikely to have intrinsic toxicity even at high doses. For patients with advanced cirrhosis, glutamine supplementation may exacerbate hepatic encephalopathy. Glutamine is metabolized into glutamate and ammonia, which may overburden the liver's ability to clear ammonia in patients with severe liver dysfunction. Studies have shown that intake of 10 to 20 grams of glutamine leads to elevated serum ammonia levels and exacerbates psychometric indicators of hepatic encephalopathy in patients with decompensated cirrhosis. For patients with normal liver function, glutamine supplementation does not lead to an increase in plasma ammonia levels, and its effect on patients with cirrhosis is not caused by liver injury. However, L-glutamine should be avoided in patients with sickle cell disease and advanced cirrhosis. Probability score: E (unlikely a cause of acute liver injury with jaundice).
Interactions
Radiation therapy is commonly used to treat prostate cancer, but it often has adverse effects on normal bladders. The authors used a pelvic radiation animal model to investigate whether glutamine supplementation could prevent radiation-induced bladder injury, particularly damage to the bladder surface. Three- to four-month-old male rats were divided into three groups of eight each: a control group (intact animals); a group receiving only radiation (10 Gy, irradiated to the pelvic and abdominal region), sacrificed 7 days (R7) or 15 days (R15) after radiation; and a group receiving radiation and supplemented with L-glutamine (0.65 g/kg body weight/day) (sacrificed 7 days (RG7) or 15 days (RG15) after radiation). Subsequently, histological measurements were performed on cells and blood vessels in the lamina propria of the bladder and the urothelial lining. The effects of radiation were assessed by comparing the control group with the R7 or R15 groups, and the protective effect of glutamine was assessed by comparing the R7 group with the RG7 group and the R15 group with the RG15 group. Results showed that in the R7 group, epithelial thickness, epithelial cell density, and lamina propria cell density were not significantly affected. However, blood vessel density decreased by 48% in the R7 group (p<0.05), and glutamine significantly inhibited this change (p<0.02). In the R15 group, lamina propria blood vessel density did not change significantly. However, epithelial thickness decreased by 25% in the R15 group (p<0.05), and glutamine inhibited this change (p<0.01). Epithelial cell density increased by 35% in the R15 group (p<0.02), but glutamine failed to prevent this radiation-induced increase in cell density. Lamina propria cell density was also unaffected in the R15 group. The density of mast cells in the lamina propria was significantly reduced in both groups R7 and R15. The density remained reduced in the RG7 group, but was higher in the RG15 group, suggesting glutamine-mediated recovery. α-actin-positive cells in the lamina propria formed the urothelial layer and were identified as myofibroblasts. The thickness of this layer increased in the R7 group, while the RG7 group was similar to the control group, and the changes in the R15 and RG15 groups were less pronounced. In summary, pelvic radiotherapy leads to significant acute and subacute changes in the composition and structural characteristics of the bladder lamina propria and epithelium. However, most of these changes can be prevented by glutamine supplementation. Therefore, these results highlight the potential use of this amino acid as a radioprotective agent. Glutamine is a neutral amino acid utilized by rapidly dividing cells such as erythrocytes, lymphocytes, and fibroblasts. It is also a substrate for glutathione synthesis. Under normal metabolic levels, glutamine is an endogenously synthesized amino acid, but in hypermetabolic states such as cancer, it must be supplemented exogenously. Animal studies have strongly demonstrated that glutamine can protect the mucosa of the upper and lower gastrointestinal tracts from the effects of chemotherapy, radiotherapy, or other damaging factors. This study aimed to investigate the protective effect of glutamine against radiation-induced diarrhea. Patients were randomly assigned to either a glutamine treatment group or a placebo group. The glutamine treatment group received 15 grams of glutamine orally three times daily. The severity of diarrhea, the need for loperamide, the need for supportive parenteral therapy, and treatment interruption due to diarrhea were assessed according to the National Cancer Institute General Toxicity Criteria, Version 3.0. There was no significant difference in the overall incidence of diarrhea between the two groups. When assessing diarrhea grades, no patients in the glutamine treatment group experienced grade 3-4 diarrhea, while 69% of patients in the placebo group experienced grade 3-4 diarrhea. In the placebo group, 39% and 92% of patients, respectively, required loperamide and parenteral supportive therapy. No treatment interruptions occurred in the glutamine treatment group. Glutamine may have a protective effect against severe radiation-induced diarrhea.

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Non-human toxicity values
Oral LD50 in mice: 700 mg/kg
Oral LD50 in rats: 7500 mg/kg

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019;53(2):211-216.

[2]. Glutamine Regulates Expression of Key Transcription Factor, Signal Transduction, Metabolic Gene, and Protein Expression in a Clonal Pancreatic Beta-Cell Line. J Endocrinol. 2006 Sep;190(3):719-27.

[3]. Glutamine and glutamate as vital metabolites. Braz J Med Biol Res. 2003 Feb;36(2):153-63. Epub 2003 Jan 29.

Therapeutic Uses
Exploratory treatment of glutamine depletion can negatively impact intestinal integrity and lead to immunosuppression. Very low birth weight (VLBW) infants are susceptible to glutamine depletion due to limited enteral nutrition in the first few weeks after birth. Enteral glutamine supplementation may have positive effects on feeding tolerance, infection incidence, and short-term prognosis. This study aimed to determine the effect of enteral glutamine supplementation on plasma amino acid concentrations, reflecting the safety of enteral glutamine supplementation in VLBW infants. In a double-blind, placebo-controlled, randomized controlled trial, VLBW infants (gestational age <32 weeks or birth weight <1500 g) received enteral glutamine supplementation (0.3 g/kg/day) or an isonitrogenous placebo (alanine) from day 3 to day 30 after birth. The supplement was added to breast milk or preterm formula. Plasma amino acid concentrations were measured at four time points: before the start of the study and at days 7, 14, and 30 after birth. There were no differences in baseline patient and nutritional characteristics between the glutamine group (n = 52) and the control group (n = 50). During the study period, plasma concentrations of most essential and non-essential amino acids were elevated. Enteral glutamine supplementation had no effect. In particular, there were no differences in the elevation of plasma glutamine and glutamate concentrations between the treatment groups (day 30, P values 0.49 and 0.34, respectively). In very low birth weight infants, enteral glutamine supplementation did not alter plasma concentrations of glutamine, glutamate, or other amino acids. For very low birth weight infants, a daily enteral supplementation dose of 0.3 g/kg appears to be safe.
Exploratory treatment of critically ill patients involves considerable oxidative stress. Glutamine and antioxidant supplementation may have therapeutic benefits, but current data are inconsistent. In this double-blind 2×2 factorial trial, we randomized 1223 critically ill adult patients with multiple organ failure on mechanical ventilation from 40 intensive care units (ICUs) in Canada, the United States, and Europe to either glutamine, an antioxidant, a combination of both, or a placebo group. Supplements were initiated within 24 hours of ICU admission via intravenous or enteral administration. The primary endpoint was 28-day mortality. Due to the interim analysis protocol, a p-value less than 0.044 was considered statistically significant at the final analysis. Patients receiving glutamine showed a trend toward higher 28-day mortality compared to those not receiving glutamine (32.4% vs. 27.2%; adjusted odds ratio 1.28; 95% confidence interval [CI] 1.00–1.64; P = 0.05). In-hospital and 6-month mortality rates were significantly higher in patients receiving glutamine than in those not receiving glutamine. Glutamine had no effect on the incidence of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, compared to 28.8% in the group not receiving antioxidant treatment; adjusted odds ratio 1.09; 95% CI 0.86 to 1.40; P = 0.48) or any other secondary endpoint. There were no differences between the groups in terms of serious adverse events (P = 0.83). Early supplementation with glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with increased mortality in critically ill patients with multiple organ failure. NutreStore (L-glutamine oral solution powder) is indicated for patients with short bowel syndrome (SBS) receiving special nutritional support, in combination with recombinant human growth hormone approved for this indication. /US product label contains/

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Drug Warnings
The safety and efficacy of L-glutamine in pediatric patients have not been established.
It is unknown whether L-glutamine is excreted into human breast milk. Because many drugs are excreted into human breast milk, caution should be exercised when breastfeeding women take L-glutamine.
Glutamine is metabolized into glutamate and ammonia. Glutamate and ammonia levels may be elevated in patients with hepatic impairment. Therefore, routine monitoring of renal and hepatic function is recommended for patients receiving parenteral nutrition (IPN) and NutreStore, especially those with renal or hepatic impairment.
FDA Pregnancy Risk Category: C / Risk cannot be ruled out. There is a lack of adequate, well-controlled human studies, and animal studies have not shown any risk to the fetus or lack relevant data. Taking this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. /
For more complete data on drug warnings for glutamine (7 of 7), please visit the HSDB record page.

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Pharmacodynamics
Like other amino acids, glutamine is a biochemically important component of proteins. Glutamine is also crucial in nitrogen metabolism. Ammonia (formed by nitrogen fixation) is assimilated into organic compounds by converting glutamate into glutamine. The enzyme that performs this process is called glutamine synthase. Glutamine can then serve as a nitrogen donor in the biosynthesis of a variety of compounds, including other amino acids, purines, and pyrimidines. L-Glutamine can increase the redox potential of nicotinamide adenine dinucleotide (NAD).

13C5H10N2O3

151.11

146.069

184161-19-1

L-Glutamine;56-85-9

5961

White to off-white solid powder

185°C (dec.) (lit.)

0.064

3

4

4

10

146

1

C(CC(=O)N)[C@@H](C(=O)O)N

ZDXPYRJPNDTMRX-VKHMYHEASA-N

InChI=1S/C5H10N2O3/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H2,7,8)(H,9,10)/t3-/m0/s1

(2S)-2,5-diamino-5-oxopentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : 31.25 mg/mL (206.80 mM)

Solubility in Formulation 1: 16.67 mg/mL (110.32 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)