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EC number: 944-552-9 | CAS number: -
In the gastrointestinal tract proteins and polypeptides are broken down into a mixture of subunits that are sufficiently small for absorption (i.e. amino acids, di-and tripeptides). Degradation of peptides within the lumen of the gastrointestinal tract may be due to instability in an acidic environment, metabolism by digestive enzymes or luminal microorganisms. Proteolysis starts in the stomach in the presence of pepsin and continues throughout the intestine. Luminal degradation of peptides is caused by enzymes released from the pancreas into the intestine (Hamman et al. 2005). For the polypeptide calcitonin (consisting of 32 amino acids and a MW of 3.4 kDa i.e. comparable to liraglutide precusor) Smart et al. (2014) reported 100% degradation during one hour in artificial intestinal fluid and after only 5 minutes in intestinal fluid from rats. For the active pharmaceutical ingredient liraglutide an oral absorption rate of 0.02% has been found in rats orally dosed in combination with a carrier expected to enhance oral absorption (Novo Nordisk 2015). Thus, oral exposure to liraglutide precusor is not expected to lead to any significant absorption due to rapid degradation in the gastrointestinal tract.
Liraglutide precursor and the read-across source substances are large proteinaceous molecule and absorption through the skin is expected to be low. Skin is generally considered as a very effective barrier for larger molecules such as polypeptides and proteins. For smaller molecules it has been shown that dermal penetration and absorption has a steep decline when the molecular size of a chemical exceeds 500 Dalton (Bos et al., 2000; Heinemann et al., 2001). An absorption at a very low percentage of insulin (a polypeptide where dermal absorption has been intensively studied) has been observed in hairless mice when applying an electrical potential across the skin (iontophoresis) with the aim of promoting the skin penetration (Heinemann et al. 2001). Thus, under normal conditions, systemic uptake from dermal exposure to insulin and similar proteins/ polypetides is considered to be very low / insignificant.
Pfister et al.(2014) reviewed data on the bioavailability of selected peptides and proteins in relation to inhalation exposure. For calcitonin having a similar molecular size as liraglutide precusor an absorption rate of 11.5-17% was found after intratracheal instillation in rats. Thus, systemic absorption to a certain extent may be expected in relation to inhalational exposure to liraglutide precursor.
For human GLP-1 a half-life in blood of < 2 minutes was found as the substance is rapidly degraded by the enzyme dipeptidyl peptidase 4. The same rapid degradation can be assumed for liraglutide precursor due to the almost identical structure.
No studies regarding identification of metabolites of liraglutide precusor or liraglutide and semaglutide have been conducted. As for human insulin a fast degradation of liraglutide precursor into inactive fragments is expected. The amino acids from the substance is expected to take part in the general metabolic pool of the body.
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