Alanine glutamine dipeptide Other names: Alanine glutamine

The dipeptide N(2)-L-alanyl-L-glutamine is endogenously split into the amino acids glutamine and alanine hereby supplying glutamine with infusion solutions for parenteral nutrition. The released amino acids flow as nutrients into their respective body pools and are metabolised according to the needs of the organism. Many disease conditions, in which clinical nutrition is indicated are accompanied by a glutamine depletion.

N(2)-L-alanyl-L-glutamine is rapidly split into alanine and glutamine after infusion. In man, half-lives of between 2.4 and 3.8 min (in terminal renal insufficiency 4.2 min) and a plasma clearance of between 1.6 and 2.7 l/min were determined. The disappearance of the dipeptide was accompanied by an equimolar increase of the corresponding free amino acids. Hydrolysis probably takes place exclusively in the extracellular space. Renal elimination of N(2)-Lalanyl-L-glutamine under constant infusion is below 5% and thus the same as that of infused amino acids.

Acute and sub-chronic toxicity

A matrix of dosage finding tests were conducted on rats and dogs over 1 to 7 days. In the rats, infusion of 50 ml/kg b.w. of a 10%, 15%, 20% and 30% solution of N(2)-L-alanyl-L-glutamine over 4h/day led to tonic spasms, increased respiratory rate and exitus. Infusion of 50 ml/kg b.w. of a 10% solution (5 g N(2)-L-alanyl-L-glutamine/kg b.w.) resulted in necrotic areas at the infusion site, reduced body weight and yellowing of the kidneys in the rats (6 h/day), and a temporary increase in heart rate in the dog (8 h/day).

Investigations were carried out in dogs (8h/day) and in rats (6h/day) with 0.5 and 1.5 g N(2)-L-alanyl-L-glutamine/kg b.w. per day i.v. over 13 weeks and with 4.5 g N(2)-L-alanyl-L-glutamine/kg b.w. per day i.v. over 6 weeks. In the dogs, vomiting occurred. With the high dose tonic or tonic-clonic cramps, increased salivation, ataxia, sedation, and lateral position were observed.

Mutagenic and tumorigenic potential

In vitro and in vivo test gave no indications of mutagenic potential. Studies investigating the tumorigenic potential were not carried out. Carcinogenic effects are not to be expected.

Reproduction toxicity

In animal trials, no indications of teratogenic or other embryotoxic and peripostnatal injuries could be observed up to a dosage of 1.6 g N(2)-L-alanyl-L-glutamine/kg b.w. per day.

Local tolerance

Following repeated i.v. infusion of N(2)-L-alanine-L-glutamine (5 and 10% solution) over 13 weeks, intolerance reactions occurred at the infusion sites (swellings, discolourations, necroses) in the rats and dogs from 0.5 g/kg b.w. onwards. Histopathologically, substance-induced inflammatory reactions with mild to fully developed dermatitis purulenta necroticans and osteomalacia of the tail vertebrae, thrombophlebitis and periphlebitis, were observed in the rats. In the dog, perivascular inflammatory reactions and, occasionally, vessel blockage were observed. The tests conducted on the dog on local tolerance after a single, intra-arterial, paravenous and intramuscular administration gave no indications of unusual intolerance reactions with incorrect administration.