Metabolism and Excretion of the Once Daily Human GLP-1 Analog liraglutide in Healthy Male Subjects and its In Vitro Degradation by Dipeptidyl Peptidase IV and Neutral Endopeptidase.
Summary of "Metabolism and Excretion of the Once Daily Human GLP-1 Analog liraglutide in Healthy Male Subjects and its In Vitro Degradation by Dipeptidyl Peptidase IV and Neutral Endopeptidase."
Liraglutide is a novel once-daily human glucagon-like peptide (GLP)-1 analog in clinical use for the treatment of type 2 diabetes. To study metabolism and excretion of [(3)H]-liraglutide, a single subcutaneous dose of 0.75 mg/14.2 MBq was given to healthy males. The recovered radioactivity in blood, urine and feces was measured and metabolites profiled. In addition, [(3)H]-liraglutide and [(3)H]-GLP-1(7-37) were incubated in vitro with dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) to compare the metabolite profiles and characterize the degradation products of liraglutide. The exposure of radioactivity in plasma (AUC(2-24 h)) was represented by liraglutide (>/=89%) and two minor metabolites (totaling =11%). Similarly to GLP-1, liraglutide was cleaved in vitro by DPP-IV in the Ala8-Glu9 position of the N-terminal and degraded by NEP into several metabolites. The chromatographic retention time of DPP-IV-truncated liraglutide correlated well with the primary human plasma metabolite [GLP-1(9-37)], and some of the NEP degradation products eluted very close to both plasma metabolites. Three minor metabolites totaling 6% and 5% of the administered radioactivity were excreted in urine and feces, respectively, but no liraglutide was detected. In conclusion, liraglutide is metabolized in vitro by DPP-IV and NEP in a similar manner to native GLP-1 although at a much slower rate. The metabolite profiles suggest that both DPP-IV and NEP are also involved in the in vivo degradation of liraglutide. The lack of intact liraglutide excreted in urine and feces and the low levels of metabolites in plasma indicate that liraglutide is completely degraded within the body.
1 Novo Nordisk A/S;
This article was published in the following journal.
Name: Drug metabolism and disposition: the biological fate of chemicals
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20709939
- DOI: http://dx.doi.org/10.1124/dmd.110.034066
Medical and Biotech [MESH] Definitions
An inorganic pyrophosphate which affects calcium metabolism in mammals. Abnormalities in its metabolism occur in some human diseases, notably HYPOPHOSPHATASIA and pseudogout (CHONDROCALCINOSIS).
A genetic disorder characterized by excretion of large amounts of OXALATES in urine; NEPHROLITHIASIS; NEPHROCALCINOSIS; early onset of RENAL FAILURE; and often a generalized deposit of CALCIUM OXALATE. There are subtypes classified by the enzyme defects in glyoxylate metabolism.
Agents that aid or increase the action of the principle drug (DRUG SYNERGISM) or that affect the absorption, mechanism of action, metabolism, or excretion of the primary drug (PHARMACOKINETICS) in such a way as to enhance its effects.
Facilities provided for human excretion, often with accompanying handwashing facilities.
Glycosides of GLUCURONIC ACID formed by the reaction of URIDINE DIPHOSPHATE GLUCURONIC ACID with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and BILIRUBIN metabolism to a more water-soluble compound that can be eliminated in the URINE and BILE.
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