L-alanil-L-glutamina

L-Alanyl-L-Glutamine

1. Identity and Chemical Character

Names and Identifiers

Alanyl-glutamine is a chemical compound which, in the form L-alanyl-L-glutamine, is used in dietary supplementation, in parenteral nutrition, and in cell culture. It is a dipeptide consisting of alanine and glutamine. The compound carries several synonyms in the scientific and commercial literature. These include alanylglutamine, H-Ala-Gln-OH, Ala-Gln, glutamine dipeptide, and the trade name Dipeptiven (intravenous form) as well as Sustamine (oral supplement form).

Its molecular formula is C₈H₁₅N₃O₄, and it is registered in PubChem under Compound ID (CID) 123935. Its Chemical Abstracts Service (CAS) registry number is 39537-23-0.

Physical and Chemical Properties

L-Alanyl-L-Glutamine appears as a white to off-white powder that is soluble in water. Its aqueous solubility is exceptionally high compared to free L-glutamine: at room temperature and one atmosphere of pressure, L-alanyl-L-glutamine has a solubility of about 586 g/L, which is more than 10 times the solubility of glutamine (35 g/L). Additionally, glutamine does not withstand sterilization procedures, whereas alanyl-glutamine does.

The outstanding aqueous stability of the dipeptide has been confirmed through controlled degradation studies. Two Ala-Gln degradation routes — the cleavage of the peptide bond and the deamination of an amide group — have been identified, and the degradation follows pseudo-first-order kinetics. The maximum stability of Ala-Gln in aqueous solution is obtained at approximately pH 6.0. The activation energy of Ala-Gln at pH 6.0 has been determined to be 27.1 kcal/mol, with a predicted shelf-life (90% remaining) of 5.3 years at 25 °C and 7.1 months at 40 °C.

Natural Sources

L-Alanyl-L-Glutamine is not found as a significant free constituent of natural foods in pharmacologically relevant quantities; rather, it is a chemically synthesized dipeptide which is degraded into L-glutamine and L-alanine in vivo for substance synthesis or energy consumption. Its two constituent amino acids — L-glutamine and L-alanine — are widely present in dietary proteins. L-glutamine can be acquired from a variety of foods including grains, dairy products, fish, and poultry. However, the dipeptide form itself, as used in clinical and sports nutrition applications, is produced synthetically.

Commercial Forms and Preparations

L-Alanyl-L-Glutamine is available in several distinct preparations depending on the clinical or consumer context:

• Intravenous (parenteral) concentrate: Its 20% intravenous injection was developed and produced by the German firm Fresenius AG, which registered and listed it in Germany in April 1995 under the trade name Dipeptamin, later registered in China in 1999 under the trade name 20% Dipeptamin.
• Oral dietary supplement powder: Marketed under the brand name Sustamine, it is the only GRAS (Generally Recognized As Safe) form of L-Alanyl-L-Glutamine approved for a variety of food, beverage, and healthcare applications.
• Cell culture media additive: In cell culture, L-alanyl-L-glutamine is sometimes used as a replacement for L-glutamine because this dipeptide is stable in aqueous solution, unlike L-glutamine, which undergoes spontaneous degradation.
• Cosmetic ingredient: It is also used in cosmetics and personal care products, where it functions primarily as a humectant and an emollient skin-conditioning agent.

2. Traditional and Historical Use

L-Alanyl-L-Glutamine is a synthetically produced compound with no traditional use within pre-modern herbal medicine or ethnopharmacology. It is a dipeptide widely used in medical and nutritional fields, but its history is entirely rooted in 20th-century biochemistry and clinical nutrition rather than in any folk, botanical, or traditional medical tradition.

The compound's development arose from a well-established problem in parenteral nutrition: in aqueous solutions, L-glutamine is relatively unstable and can degrade to form ammonia and pyroglutamic acid; however, when bonded with alanine to form L-alanyl-L-glutamine, the stability is significantly improved, thereby reducing these degradation issues. This instability of free glutamine in solution had historically prevented its inclusion in parenteral nutrition formulations, as parenteral nutritional products do not contain glutamine due to its unstable properties in aqueous solution.

The conceptual groundwork for glutamine dipeptides in parenteral nutrition was laid in the late 1980s and 1990s by researchers including P. Fürst and colleagues. The 20% intravenous injection of L-alanyl-L-glutamine was developed and produced by Fresenius AG (Germany), and in April 1995 it was registered in Germany under the name Dipeptamin. Its uptake in sports nutrition and general wellness supplementation came later, driven by parallel research on oral delivery of glutamine to athletes and patients with gastrointestinal conditions.

3. Key Constituents, Active Compounds, and Mechanisms of Action

Chemical Composition and Prodrug Character

L-alanyl-L-glutamine is a chemically synthesized dipeptide which is degraded into L-glutamine and L-alanine in vivo for substance synthesis or energy consumption inside the body. It functions essentially as a more stable delivery vehicle — or prodrug — for L-glutamine. Enzymes within the body, specifically peptidases, cleave the peptide bond in L-alanyl-L-glutamine, gradually releasing L-glutamine. This stepwise release ensures a sustained and steady supply of L-glutamine to cells and tissues, which is crucial for metabolic processes such as protein synthesis and energy production.

The slow release mechanism also prevents sudden spikes in ammonia levels, which can be detrimental to cellular function. Once hydrolyzed, both constituent amino acids exert their own physiological roles: L-glutamine as the most abundant free amino acid in blood and a critical substrate for rapidly dividing cells, and L-alanine as a gluconeogenic amino acid and energy substrate.

Pharmacokinetics

Intravenous administration of L-alanyl-L-glutamine results in rapid hydrolysis. A pharmacokinetic study in ICU patients found that the half-life of the dipeptide was 0.26 hours (range, 0.15–0.63 h), and the distribution volume of alanyl-glutamine was larger than the extracellular water volume, indicating a rapid hydrolysis of the dipeptide. During steady-state infusion, a steady state in plasma concentration was reached for alanyl-glutamine, but not for alanine, glutamine, or glutamate; there was no accumulation of any of the amino acids, as pre-infusion concentrations were reached within 8 hours after the end of infusion.

Following intravenous administration, N(2)-L-alanyl-L-glutamine is subject to rapid decomposition into glutamine and alanine in vivo, with a human plasma half-life of 2.4 to 3.8 minutes (and approximately 4.2 minutes in patients with late renal dysfunction). When the infusion volume is constant, the amount of N(2)-L-alanyl-L-glutamine excreted through urine is less than 5%, which is comparable to other infused amino acids.

Following oral administration, all modes of oral administration to healthy subjects significantly increased free plasma glutamine and alanine concentrations. Peak increments of plasma glutamine concentration were 794 ± 107 μmol/L after bolus intake of 20 g of Ala-Gln and 398 ± 61 μmol/L after intermittent intake of the same cumulative dose.

Established Mechanisms of Action

The documented biological actions of L-alanyl-L-glutamine are mediated primarily through the sustained provision of L-glutamine. Key mechanistic pathways include:

• Heat Shock Protein (HSP70) upregulation: Glutamine plays a key role in several essential metabolic processes and is an important modulator of the heat shock protein (HSP) response. The 70-kDa HSP (HSP70) expression is enhanced by glutamine via the hexosamine biosynthetic pathway, which inhibits the NF-κB pathway, regenerating and recovering myofibers through regulation of the early inflammatory response to muscle injury. In a clinical study, serum HSP70 concentrations were significantly higher in glutamine-treated ICU patients compared to controls, and HSP70 level was significantly positively correlated with glutamine level.
• Intestinal barrier and electrolyte transport enhancement: L-Alanyl-L-Glutamine appears to increase electrolyte and fluid uptake across the intestines by increasing ion transport through an enhanced signaling pathway within the intestinal mucosal cells. The protective effect on the gastrointestinal tract reduces bacterial translocation, thus reducing the risk of infections and infection-related problems such as diarrhea, dehydration, malabsorption, and electrolyte imbalance.
• Antioxidant and anti-inflammatory effects: Glutamine is the most abundant free amino acid in the human body, and it plays a key role in multiple physical processes, including interorgan nitrogen transport, cellular redox pathways, and the synthesis of glutathione, nucleotide bases, and peptides. In animal models, Ala-Gln exerted an antioxidant effect by elevating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX), and exhibited an anti-inflammatory effect by decreasing the accumulation of activated macrophages and suppressing the production of proinflammatory mediators.
• Immune system substrate provision: L-Alanyl-L-Glutamine is used extensively in in vitro experiments to understand cellular metabolism and physiology, particularly under conditions that demand sustained availability of glutamine, which is critical for rapidly dividing cells such as immune and intestinal cells.
• Protein synthesis and nitrogen balance support: After hydrolysis, both released amino acids participate in anabolic metabolism. L-glutamine serves as a nitrogen donor for nucleotide synthesis and protein anabolism, while L-alanine participates in the glucose-alanine cycle and gluconeogenesis, supporting energy homeostasis in stressed states.

4. Scientific Evidence by Area of Use

4.1 Parenteral Nutrition in Critically Ill Patients

This is the area with the most extensive and rigorously controlled human clinical evidence for L-alanyl-L-glutamine.

Key Clinical Trials

A pivotal multicenter French RCT by Déchelotte et al. (2006) studied 114 ICU patients admitted for multiple trauma, complicated surgery, or pancreatitis. The study design was a prospective, double-blind, controlled, randomized trial conducted in ICUs across 16 hospitals in France. Patients were randomized to receive isocaloric isonitrogenous TPN supplemented with either L-alanyl-L-glutamine dipeptide (0.5 g/kg/day; Ala-Gln group, n=58) or L-alanine + L-proline (control group, n=56) over at least 5 days. TPN supplemented with Ala-Gln dipeptide in ICU patients was associated with a reduced rate of infectious complications and better metabolic tolerance.

A Spanish multicenter RCT (Grau et al., 2011) enrolled 127 critically ill patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score >12 requiring parenteral nutrition for 5–9 days. The aim was to assess the clinical efficacy of alanine-glutamine dipeptide-supplemented TPN as defined by the occurrence of nosocomial infections; secondary parameters included Sequential Organ Failure Assessment (SOFA) score, hyperglycemia and insulin needs, ICU and hospital length of stay, and 6-month mortality. The design was a multicenter, prospective, double-blind, randomized trial conducted in 12 ICUs at Spanish hospitals.

An earlier RCT by Fuentes-Orozco et al. (2004) enrolled 33 patients with secondary peritonitis. Patients were randomly assigned to receive either standard TPN (n=16) or L-alanyl-L-glutamine-supplemented TPN (n=17) after medical and surgical treatment of the infectious focus, with the two TPN formulae being isonitrogenous and isocaloric, commencing the morning after surgery and running continuously for 10 consecutive days. L-Alanyl-L-Glutamine-supplemented TPN improved the infectious morbidity of patients with secondary peritonitis.

Systematic Reviews and Meta-Analyses

A rigorous systematic evaluation by Stehle et al. (published in Clinical Nutrition) applied stringent eligibility criteria, selecting only RCTs in critically ill adult patients without hepatic and/or renal failure, who were haemodynamically and metabolically stable and who received parenteral glutamine dipeptide strictly according to current clinical guidelines (via the parenteral route at 0.3–0.5 g/kg/day; maximum 30% of the prescribed nitrogen supply) in combination with adequate nutrition. The included studies involved 842 critically ill patients. Common effect estimates indicated that parenteral glutamine dipeptide supplementation significantly reduced infectious complications (relative risk [RR] = 0.70, 95% CI 0.60–0.83, p < 0.0001), ICU length of stay (mean difference −1.61 days, 95% CI −3.17 to −0.05, p = 0.04), hospital length of stay (−2.30 days, 95% CI −4.14 to −0.45, p = 0.01), and mechanical ventilation duration (−1.56 days, 95% CI −2.88 to −0.24, p = 0.02). It also lowered the hospital mortality rate by 45% (RR = 0.55, 95% CI 0.32–0.94, p = 0.03) but had no effect on ICU mortality.

The REDOXS Trial: Conflicting High-Dose Evidence

The picture for glutamine supplementation in critical care was significantly complicated by the large-scale REDOXS (Reducing Deaths due to Oxidative Stress) trial published in the New England Journal of Medicine. Using a factorial design, patients received glutamine supplementation of 0.35 g/kg/day intravenously (provided as 0.50 g of the dipeptide alanyl-glutamine [Dipeptiven, Fresenius Kabi] per kilogram per day) plus 30 g of glutamine per day given enterally. In this international, randomized, blinded trial involving critically ill patients with multiorgan failure, a nonsignificant increase in 28-day mortality and significant increases in in-hospital and 6-month mortality were observed with the use of glutamine.

Subsequent meta-analyses attempted to reconcile these discordant findings. One meta-analysis found that high-dosage glutamine supplementation caused harmful effects (including high urea levels) rather than benefits; glutamine supplementation at a dosage higher than 0.5 g/kg/day increased mortality in ICU patients. Another systematic review concluded that this meta-analysis does not suggest increased mortality with the use of enteral glutamine supplementation overall. The signals of harm in the REDOXS trial may be due to the high dose of both enteral and parenteral glutamine used, the negative effects in patients with renal failure, and the low total caloric and protein intake, although these factors remain speculative.

Evidence strength summary: For parenteral L-alanyl-L-glutamine supplementation at guideline-recommended doses (0.3–0.5 g/kg/day) in appropriately selected critically ill patients without renal or hepatic failure, multiple RCTs and meta-analyses support reduced infectious complications and shorter hospital stay. However, a major RCT (REDOXS) using higher combined enteral + parenteral doses found potential harm in patients with multi-organ failure. Current clinical guidance (as of the 2016 SCCM/ASPEN guidelines) does not recommend supplemental glutamine for routine use in either enteral or parenteral regimens. Evidence is therefore mixed to moderate in selected populations and negative in undifferentiated high-risk critically ill patients at pharmacological doses.

4.2 Perioperative and Surgical Settings

Several RCTs have assessed L-alanyl-L-glutamine as a peri- and post-operative TPN additive. A randomized controlled trial in patients undergoing colonic cancer resection evaluated the impact of dipeptide alanyl-L-glutamine supplementation on glucose-insulin homeostasis, inflammatory mediators, and surgical recovery. Sixty patients were randomized to receive physiological saline, a compound amino acid solution (8.5% 18AA-II), or glutamine 0.5 g/kg, given 24 hours before and 1 hour after the start of the surgical procedure.

Earlier work by Mertes et al. (2000) examined cost containment through L-alanyl-L-glutamine-supplemented TPN after major abdominal surgery in a prospective, randomized, double-blind, controlled study. Meta-analyses encompassing surgical ICU patients found that in the surgical ICU subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.70, 95% CI 0.52–0.94, p = 0.04).

Evidence strength: Moderate. Multiple RCTs in surgical patients receiving parenteral nutrition supplement with Ala-Gln suggest reductions in infectious morbidity. Evidence is stronger in this context than in undifferentiated medical ICU populations.

4.3 Sports Performance, Hydration, and Exercise

L-Alanyl-L-Glutamine has been investigated as an oral supplement for athletes, primarily under the commercially branded preparation Sustamine.

A crossover study by Hoffman et al. (2010), published in the Journal of the International Society of Sports Nutrition, examined the effects of two oral doses during endurance exercise under hydration stress. The study examined the effect of acute L-alanyl-L-glutamine (Sustamine™) ingestion on performance changes and markers of fluid regulation, immune, inflammatory, oxidative stress, and recovery in response to exhaustive endurance exercise. Ten physically active males (20.8 ± 0.6 years; 77.4 ± 10.5 kg; 12.3 ± 4.6% body fat) participated. In four subsequent randomly ordered trials, subjects dehydrated to −2.5% of their baseline body mass. In one trial subjects were not rehydrated; in the subsequent three trials, subjects rehydrated to −1.5% of their baseline body mass by drinking either water or two different doses (0.05 g/kg and 0.2 g/kg, respectively) of the AG supplement. Results demonstrated that AG supplementation provided a significant ergogenic benefit by increasing time to exhaustion during a mild hydration stress. No significant differences were observed between trials in CRP, IL-6, MDA, or in any other hormonal or biochemical measures.

A separate study by the same research group assessed one-hour run performance. The study examined the efficacy of L-alanyl-L-glutamine ingestion with a commercially available sports drink compared to the sports drink only on time to exhaustion during prolonged endurance exercise. Twelve endurance-trained men (23.5 ± 3.7 years) performed four trials, each consisting of a 1-hour treadmill run at 75% VO₂peak followed by a run to exhaustion at 90% VO₂peak. One trial consisted of no hydration, another used a sports drink alone, and two trials used a low dose (300 mg/500 mL) and a high dose (1 g/500 mL) of L-alanyl-L-glutamine added to the sports drink. Results indicated that ingestion of the alanine-glutamine dipeptide at either the low or high dose significantly improved time to exhaustion during high-intensity exercise compared to the sports drink alone.

A basketball performance study used a similar design. During one trial subjects consumed only water, while during two other trials subjects consumed the AG supplement mixed in water using either a low dose (1 g per 500 mL) or a high dose (2 g per 500 mL) concentration.

Regarding muscle recovery, studies show that chronic oral administration of free L-glutamine or the dipeptide can attenuate the injury and inflammation induced by intense aerobic and exhaustive exercise.

Evidence strength: Preliminary to moderate. Sports-focused trials are small (n = 10–12 per study), conducted predominantly in young healthy males by the same research group, and do not consistently control for commercial interest. The mechanism involving ion transport enhancement is plausible but has not been confirmed in large independent RCTs. This evidence base warrants independent replication before firm conclusions can be drawn.

4.4 Gastrointestinal Health and Intestinal Permeability

L-Alanyl-L-Glutamine has been specifically studied in populations with compromised intestinal barrier function, including HIV/AIDS patients with diarrhea, malnourished children, and patients with C. difficile infection.

A randomized, double-blind, placebo-controlled trial in HIV/AIDS patients assessed oral alanyl-glutamine. The study used isonitrogenous doses of alanyl-glutamine (24 g/day) and placebo (glycine, 25 g/day) for 10 days. Forty-six patients with HIV/AIDS (36 male; mean age 37.28 ± 3 years) were enrolled, with 22 treated with alanyl-glutamine and 24 with glycine. Lactulose and mannitol urinary excretion were measured by high-performance liquid chromatography before and after supplementation. There was a significant increase in mannitol urinary excretion in the group treated with alanyl-glutamine, suggesting improved intestinal absorption. The authors concluded that nutritional supplementation with alanyl-glutamine was associated with an improvement in intestinal absorption, particularly in patients who had recently experienced diarrhea.

ClinicalTrials.gov records a double-blind RCT in children with persistent diarrhea or malnutrition, which sought to determine the effect of 7 days of supplementation of alanyl-glutamine (compared to glycine) on damaged intestinal barrier function measured by the lactulose/mannitol test, as well as on diarrhea frequency, weight gain, and intestinal inflammation.

A broader 2024 systematic review and meta-analysis of 10 RCTs (352 participants, 1998–2014) on glutamine supplementation and gastrointestinal permeability found that overall, glutamine supplementation did not significantly affect intestinal permeability (WMD: −0.00, 95% CI −0.04 to 0.03). Subgroup analysis showed a significant reduction in intestinal permeability with doses over 30 g/day (WMD: −0.01, 95% CI −0.10 to −0.08).

Evidence strength: Preliminary to moderate for specific at-risk populations (HIV/AIDS, post-infectious enteropathy, surgical patients). The overall evidence across general populations using glutamine (including the dipeptide form) is mixed, with benefit appearing more prominent at higher doses and in states of established gut barrier compromise.

4.5 Body Composition in Chronic Disease (Heart Failure)

In a randomized double-blind, placebo-controlled trial, 31 heart failure patients were randomized to either L-alanyl-L-glutamine (8 g/day) and PUFA (6.5 g/day) or placebo (safflower oil and milk powder) for 3 months. Cardiopulmonary exercise testing, dual-energy X-ray absorptiometry, 6-minute walk test, hand grip strength, functional muscle testing, echocardiography, quality of life, and lateral quadriceps muscle biopsy were performed at baseline and follow-up. Oxidative capacity and metabolic gene expression were analyzed on muscle biopsies. The combined supplementation of L-alanyl-L-glutamine and polyunsaturated fatty acid did not improve exercise performance or muscle function but increased lean body mass and quality of life. This study cannot isolate the specific contribution of L-alanyl-L-glutamine, as it was combined with fish oil.

Evidence strength: Very preliminary. Single small RCT; confounded by co-intervention with omega-3 fatty acids; the contribution of L-alanyl-L-glutamine alone cannot be assessed.

4.6 Animal and Preclinical Evidence (Not Directly Transferable to Humans)

A number of studies have provided mechanistic insights from animal and in vitro models. In a murine model of lipopolysaccharide-induced acute liver injury, Ala-Gln treatment significantly attenuated hepatic pathological changes, lowered NAFLD activity score, reduced plasma ALT, AST, and LDH levels, and dramatically alleviated lipid accumulation in liver through modulating the expression levels of fatty acid translocase (FAT/CD36) and farnesoid X receptor (FXR). Notably, Ala-Gln also suppressed the development of liver fibrosis in MCD-diet-fed mice, possibly through inhibition of hepatic stellate cell activation. These findings are animal data and should not be assumed to translate directly to clinical outcomes in humans.

5. Body Systems and Health Areas

Based on the available clinical and preclinical literature, L-alanyl-L-glutamine is associated with actions across several body systems:

• Gastrointestinal system: Intestinal barrier integrity; reduction of bacterial translocation; electrolyte absorption and anti-diarrheal effects; mucosal fuel provision to enterocytes.
• Immune system: Provision of glutamine as a critical substrate for lymphocytes and macrophages; modulation of HSP70-mediated stress responses; potential reduction of infectious complications in perioperative and ICU settings.
• Musculoskeletal system: Attenuation of exercise-induced muscle damage; modulation of inflammatory response; nitrogen supply for protein synthesis; supporting lean body mass in catabolic disease states.
• Metabolic/endocrine: Interaction with glucose-insulin homeostasis in surgical patients; glutamine as a gluconeogenic precursor; contribution to nitrogen balance.
• Hepatic system (preclinical): Animal data suggest antioxidant and anti-inflammatory effects in liver injury models, including reduction of fibrosis markers and normalization of liver enzymes.
• Fluid and electrolyte regulation: Enhancement of intestinal ion transport; support of hydration status during physical exertion.

6. Dosage Forms and Reported Dosages

The following dosages are drawn exclusively from published study protocols and should not be interpreted as prescriptive recommendations:

• Parenteral (intravenous) — critical care / surgical nutrition:
  • Guideline-compliant dose range in RCTs: 0.3–0.5 g/kg/day, constituting a maximum of 30% of prescribed nitrogen supply, combined with adequate background nutrition.
  • The French multicenter RCT used 0.5 g/kg/day of L-alanyl-L-glutamine dipeptide as the experimental intervention, delivered via central venous catheter over at least 5 days.
  • A pharmacokinetic study administered 0.5 g/kg/day undiluted alanyl-glutamine (20%) or saline peripherally over 4 hours in ICU patients (n = 20).
  • The REDOXS trial used 0.35 g/kg/day intravenously (provided as 0.50 g/kg/day of the dipeptide Dipeptiven) plus 30 g of glutamine enterally — a dosing strategy subsequently associated with potential harm in multi-organ failure patients.
• Oral — sports/exercise supplementation:
  • Two doses were tested in the Hoffman et al. endurance exercise study: 0.05 g/kg and 0.2 g/kg, consumed during rehydration to −1.5% body mass following 2.5% dehydration.
  • A one-hour run performance study tested a low dose of 300 mg/500 mL and a high dose of 1 g/500 mL added to a sports drink, with 250 mL consumed every 15 minutes during exercise.
  • A basketball performance study used 1 g per 500 mL (low dose) or 2 g per 500 mL (high dose) mixed in water.
• Oral — gut/immune supplementation:
  • The HIV/AIDS intestinal permeability RCT used 24 g/day of alanyl-glutamine for 10 days.
  • A pharmacokinetic study in healthy adults administered a fixed oral dose of 20 g of L-Ala-Gln, containing approximately 13 g of glutamine.
• Oral — heart failure (combined intervention):
  • The heart failure RCT used 8 g/day of L-alanyl-L-glutamine (combined with 6.5 g/day of PUFA) for 3 months.

7. Safety Considerations and Interactions

General Safety Profile in Studied Doses

Per review of clinical trials specifically addressing safety, glutamine at doses of up to 60 g/day given for as short as 4 hours to up to 30 days, administered to healthy volunteers, bone marrow transplant patients, or preterm neonates, was considered safe and not associated with adverse events.

Contraindications

L-alanyl-L-glutamine should not be administered to patients with severe renal insufficiency (creatinine clearance [CrCl] <25 mL/min), severe hepatic insufficiency, or severe metabolic acidosis. The mechanistic basis for the renal and hepatic contraindications relates to the metabolism of the dipeptide's breakdown products: patients with liver disease may have decreased ammonia excretion and may be predisposed to accumulation of ammonia, a breakdown product of glutamine. Similarly, patients with kidney disease may have decreased renal excretion of ammonia and glutamic acid.

High-Dose Risk in Critical Illness

The REDOXS trial established that high-dose combined enteral and parenteral glutamine administration is associated with harm in critically ill patients with multi-organ failure. The REDOXS study observed significantly increased in-hospital and six-month mortality rates with the use of glutamine, without reducing the nosocomial infection rate in ICU patients with multi-organ failure. Meta-analysis confirmed that in the high-dosage subgroup (above 0.5 g/kg/day), the mortality rate in the glutamine group was significantly higher than that of the control group (RR 1.18; 95% CI 1.02–1.38; p = 0.03). This strategy turned out to be harmful, possibly attributable to the pharmacological doses of glutamine used. Because glutamine supplementation given to the right patients in the right doses may be helpful, this result imposes the risk of undermining the overall glutamine supplementation concept.

Liver Enzyme Elevations

Two patients who developed high concentrations of liver enzymes were withdrawn from one study; these resolved after discontinuing treatment. No other adverse effects were observed, but the authors noted concern regarding the possibility of liver toxicity. The elevated liver enzymes might, however, have been a complication of intravenous nutrition rather than of glutamine per se, because no control group without supplementation was studied in parallel.

Potential Oxalate Considerations

There is also the possibility that calcium oxalate stone formation in the kidney might be increased with high amino acid intake. Although several studies have supported this hypothesis, the only long-term prospective trial of chronic protein restriction (4.5 years) on stone formation in patients newly diagnosed with calcium stones did not confirm it.

Hypersensitivity

Glutamine peptides are contraindicated in those hypersensitive to any component of L-alanyl-L-glutamine.

Known Drug Interactions

Based on available sources, no formal drug–drug or drug–food pharmacokinetic interactions have been identified for L-alanyl-L-glutamine as a distinct entity. The principal safety concern relates to patient-disease interactions rather than drug–drug interactions.

References

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