DT-Web

DB06655 - Liraglutide


Identification
Name Liraglutide
Accession Number DB06655
Type biotech
Description Victoza contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae, has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 3751.2 Da
Groups approved
Monoisotopic Weight Not Available
Pharmacology
Indication For use in/treatment of diabetes mellitus type 2.
Mechanism of action Liraglutide is an acylated GLP-1 (Glucagon-Like Peptide-1) receptor agonist. Liraglutide upregulates intracellular cAMP resulting in the release of insulin given elevated blood glucose concentrations. Glucagon secretion is also decreased in a glucose-dependent fashion by liraglutide.
Absorption Maximum concentrations of liraglutide are achieved at 8-12 hours after dose. The mean peak and total exposures of liraglutide were 35 ng/mL and 960 ng?h/mL, respectively, for a subQ single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0-? was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0-? from thigh was 22% lower than that from abdomen. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.
Protein binding >98%
Biotransformation During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.
Route of elimination Excreted in urine and feces, 6% and 5%, respectively.
Toxicity In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. RISK OF THYROID C-CELL TUMORS
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Acetaminophen These agents may have decreased C max and a delayed T max during coadministration.
Atorvastatin These agents may have decreased C max and a delayed T max during coadministration.
Azilsartan medoxomil Pharmacodynamic synergist- increases effects. May also increase hypoglycemic effects by improving insulin sensitivity.
Digoxin These agents may have decreased C max and a delayed T max during coadministration.
Griseofulvin Cmax may be increased.
Insulin Regular Coadministration may increase the risk of hypoglycemia. A lower dose of the antidiabetic agent may be needed.
Somatropin recombinant Somatropin may antagonize the hypoglycemic effect of liraglutide. Monitor for changes in fasting and postprandial blood sugars.
Food Interactions Not Available

Targets


Glucagon-like peptide 1 receptor
Name Glucagon-like peptide 1 receptor
Gene Name GLP1R
Pharmacological action yes
Actions agonist
References
  • Bock T, Pakkenberg B, Buschard K: The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211. APMIS. 2003 Dec;111(12):1117-24. - Pubmed
  • Larsen PJ, Wulff EM, Gotfredsen CF, Brand CL, Sturis J, Vrang N, Knudsen LB, Lykkegaard K: Combination of the insulin sensitizer, pioglitazone, and the long-acting GLP-1 human analog, liraglutide, exerts potent synergistic glucose-lowering efficacy in severely diabetic ZDF rats. Diabetes Obes Metab. 2008 Apr;10(4):301-11. - Pubmed
DTHybrid score 1.2167

Enzymes


Dipeptidyl peptidase 4
Name Dipeptidyl peptidase 4
Gene Name DPP4
Actions substrate
References
  • Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, van Lier JJ, Zdravkovic M, Olsen AK: Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010 Nov;38(11):1944-53. doi: 10.1124/dmd.110.034066. Epub 2010 Aug 13. - Pubmed
DTHybrid score 1.8439
Neprilysin
Name Neprilysin
Gene Name MME
Actions substrate
References
  • Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, van Lier JJ, Zdravkovic M, Olsen AK: Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010 Nov;38(11):1944-53. doi: 10.1124/dmd.110.034066. Epub 2010 Aug 13. - Pubmed
DTHybrid score 1.5023

Predictions


Id Partner name Gene Name Score
584 Glucagon receptor GCGR 0.2376
3857 Glucagon-like peptide 2 receptor GLP2R 0.206
3060 Leukotriene A-4 hydrolase LTA4H 0.0863
244 Angiotensin-converting enzyme ACE 0.0679
6285 Thermolysin npr 0.0648
2457 Bacillolysin nprS 0.0635
5660 Esterase EstB estB 0.0178
4512 Cytochrome P450 3A4 CYP3A4 0.0162
3095 Complement factor B CFB 0.0155
2517 Subtilisin BPN' apr 0.0129
4681 Aminopeptidase Not Available 0.0114
3526 Pseudomonalisin pcp 0.0114
1588 Multidrug resistance protein 1 ABCB1 0.0104
6231 Pepsin A PGA3 0.0093
2300 Lysozyme E 0.0071
3633 Lysozyme R 0.0071
5597 Lysozyme 17 0.0071
4119 Cytochrome P450 2D6 CYP2D6 0.006
6150 Solute carrier organic anion transporter family member 4C1 SLCO4C1 0.0052
4924 Cytochrome P450 2C8 CYP2C8 0.0052
862 Multidrug resistance-associated protein 1 ABCC1 0.0048
4118 Cytochrome P450 3A5 CYP3A5 0.0037
6142 Solute carrier family 22 member 8 SLC22A8 0.0036
6220 Aryl hydrocarbon receptor AHR 0.0016
631 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR 0.0015
3387 3-hydroxy-3-methylglutaryl-coenzyme A reductase mvaA 0.0015
6136 Multidrug resistance-associated protein 5 ABCC5 0.0012
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0012
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0012
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0012
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0011
4878 Glycoprotein hormones alpha chain CGA 0.0011
1052 Cytotoxic T-lymphocyte protein 4 CTLA4 0.0011
1072 Granzyme B GZMB 0.0011
4882 Dipeptidyl aminopeptidase-like protein 6 DPP6 0.0011
4877 Beta-mannanase man 0.0011
4871 Endo-beta-N-acetylglucosaminidase F3 endOF3 0.0011
4856 CD209 antigen CD209 0.0011
4889 Ig epsilon chain C region IGHE 0.0011
4189 Alpha-galactosidase A GLA 0.0011
4869 Major capsid protein A430L 0.0011
4852 Reticulon-4 receptor RTN4R 0.0011
4880 Membrane cofactor protein CD46 0.0011
4845 ADAM 33 ADAM33 0.0011
757 Fusion glycoprotein F0 F 0.0011
4875 Fusion glycoprotein F0 F 0.0011
4721 Beta-1,4-mannanase manA 0.0011
4850 Beta-2-glycoprotein 1 APOH 0.0011
1563 Platelet glycoprotein Ib alpha chain GP1BA 0.0011
1354 Beta-glucuronidase GUSB 0.0011
442 Envelope glycoprotein gp41 0.0011
4859 Envelope glycoprotein env 0.0011
3352 Structural polyprotein Not Available 0.0011
3628 Structural polyprotein Not Available 0.0011
4892 Structural polyprotein Not Available 0.0011
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0011
2164 Multidrug resistance-associated protein 4 ABCC4 0.001
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.001
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.001
793 T-cell surface antigen CD2 CD2 0.001
4193 Atrial natriuretic peptide clearance receptor NPR3 0.001
4861 Interleukin-6 receptor alpha chain IL6R 0.001
119 Carcinoembryonic antigen-related cell adhesion molecule 1 CEACAM1 0.001
3837 Cytokine receptor common beta chain CSF2RB 0.001
1379 Interleukin-12 subunit beta IL12B 0.0009
4890 Hemagglutinin HA 0.0009
6566 Hemagglutinin Not Available 0.0009
4857 Zinc-alpha-2-glycoprotein AZGP1 0.0009
6858 Inactive carboxylesterase 4 CES1P1 0.0009
1184 Interferon beta IFNB1 0.0009
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0009
2998 Sialic acid-binding Ig-like lectin 7 SIGLEC7 0.0009
6120 Cation-independent mannose-6-phosphate receptor IGF2R 0.0009
2297 Genome polyprotein Not Available 0.0009
2322 Genome polyprotein Not Available 0.0009
2694 Genome polyprotein Not Available 0.0009
2719 Genome polyprotein Not Available 0.0009
2860 Genome polyprotein Not Available 0.0009
2928 Genome polyprotein Not Available 0.0009
3160 Genome polyprotein Not Available 0.0009
3260 Genome polyprotein Not Available 0.0009
4783 Genome polyprotein Not Available 0.0009
5726 Genome polyprotein Not Available 0.0009
5779 Genome polyprotein Not Available 0.0009
5867 Genome polyprotein Not Available 0.0009
6253 Genome polyprotein Not Available 0.0009
6301 Genome polyprotein Not Available 0.0009
6380 Genome polyprotein Not Available 0.0009
6381 Genome polyprotein Not Available 0.0009
6437 Genome polyprotein Not Available 0.0009
6520 Genome polyprotein Not Available 0.0009
6521 Genome polyprotein Not Available 0.0009
6652 Genome polyprotein Not Available 0.0009
6734 Genome polyprotein Not Available 0.0009
6735 Genome polyprotein Not Available 0.0009
6736 Genome polyprotein Not Available 0.0009
6737 Genome polyprotein Not Available 0.0009
6738 Genome polyprotein Not Available 0.0009
6739 Genome polyprotein Not Available 0.0009
6744 Genome polyprotein Not Available 0.0009
6748 Genome polyprotein Not Available 0.0009
6894 Genome polyprotein Not Available 0.0009
6898 Genome polyprotein Not Available 0.0009
1859 Prostatic acid phosphatase ACPP 0.0009
3444 Cyanovirin-N Not Available 0.0009
3140 Hemagglutinin-neuraminidase HN 0.0009
3609 Hemagglutinin-neuraminidase HN 0.0009
3258 Mannosyl-oligosaccharide alpha-1,2-mannosidase MSDC 0.0009
6030 Cytochrome P450 2B6 CYP2B6 0.0008
4787 Envelope glycoprotein gp160 env 0.0008
4820 Envelope glycoprotein gp160 env 0.0008
5727 Envelope glycoprotein gp160 env 0.0008
4666 Fucose-binding lectin PA-IIL lecB 0.0008
2372 Bifunctional tail protein 9 0.0008
6107 Cytochrome P450 3A7 CYP3A7 0.0008
2577 Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase MAN1B1 0.0008
18 High affinity immunoglobulin epsilon receptor subunit alpha FCER1A 0.0008
554 Low-density lipoprotein receptor LDLR 0.0008
852 Heparin cofactor 2 SERPIND1 0.0008
3480 Mannan endo-1,4-beta-mannosidase manA 0.0008
64 Neuraminidase NA 0.0008
641 Neuraminidase NA 0.0008
2676 Neuraminidase NA 0.0008
3026 Neuraminidase NA 0.0008
3519 Neuraminidase NA 0.0008
6007 Neuraminidase NA 0.0008
1439 Lactotransferrin LTF 0.0007
6016 Cytochrome P450 2C19 CYP2C19 0.0007
1243 Cathepsin D CTSD 0.0007
595 Fibrinogen alpha chain FGA 0.0007
4757 Cytochrome P450 2C9 CYP2C9 0.0007
958 Insulin-like growth factor 1 receptor IGF1R 0.0007
2430 Chondroitinase B cslB 0.0007
1782 Neutrophil gelatinase-associated lipocalin LCN2 0.0007
6307 Ig gamma-2 chain C region IGHG2 0.0007
2581 Chondroitinase AC cslA 0.0007
6500 Phospholipase A2 PLA2G1B 0.0007
6847 Lactase-phlorizin hydrolase LCT 0.0007
3814 Complement C1r subcomponent C1R 0.0006
2207 Rhodopsin RHO 0.0006
309 Antithrombin-III SERPINC1 0.0006
4785 Ig gamma-1 chain C region IGHG1 0.0006
76 Nitric-oxide synthase, brain NOS1 0.0005
4604 Liver carboxylesterase 1 CES1 0.0005
3923 Cholinesterase BCHE 0.0004
20 Prostaglandin G/H synthase 1 PTGS1 0.0003
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