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Identification
Name Sibutramine
Accession Number DB01105 (APRD00456)
Type small molecule
Groups illicit, approved, withdrawn
Description

Sibutramine (trade name Meridia in the USA, Reductil in Europe and other countries), usually as sibutramide hydrochloride monohydrate, is an orally administered agent for the treatment of obesity. It is a centrally acting stimulant chemically related to amphetamines. Sibutramine is classified as a Schedule IV controlled substance in the United States. In October 2010, Sibutramine was withdrawn from Canadian and U.S. markets due to concerns that the drug increases the risk of heart attack and stroke in patients with a history of heart disease.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Sibutramina [Spanish]
  • Sibutraminum [Latin]
Brand names
  • Butramin
  • Medaria
  • Meridia (Abbott Laboratories, Inc.)
  • Reductil
Brand name mixtures Not Available
Categories
  • Antidepressants
  • Appetite Depressants
  • Anorexigenic Agents
  • Stimulants
  • Antidepressive Agents
CAS number 106650-56-0
Weight Average: 279.848
Monoisotopic: 279.175377544
Chemical Formula C17H26ClN
InChI Key InChIKey=UNAANXDKBXWMLN-UHFFFAOYSA-N
InChI
InChI=1S/C17H26ClN/c1-13(2)12-16(19(3)4)17(10-5-11-17)14-6-8-15(18)9-7-14/h6-9,13,16H,5,10-12H2,1-4H3
Plain Text
IUPAC Name
{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}dimethylamine
SMILES
CC(C)CC(N(C)C)C1(CCC1)C1=CC=C(Cl)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenethylamines
  • Amphetamines
Substructures
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Aliphatic and Aryl Amines
  • Cyclobutane and Derivatives
  • Phenethylamines
  • Aromatic compounds
  • Amphetamines
Pharmacology
Indication For the treatment of obesity.
Pharmacodynamics Sibutramine is an orally administered agent for the treatment of obesity. Sibutramine exerts its pharmacological actions predominantly via its secondary (M1) and primary (M2) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin and norepinephrine reuptake in vivo, but not in vitro. However, metabolites M1 and M2 inhibit the reuptake of these neurotransmitters both in vitro and in vivo. In human brain tissue, M1 and M2 also inhibit dopamine reuptake in vitro, but with ~3-fold lower potency than for the reuptake inhibition of serotonin or norepinephrine. Sibutramine, M1 and M2 exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M1 and M2 have low affinity for serotonin (5-HT1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), norepinephrine (b, b1, b3, a1 and a2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.
Mechanism of action Sibutramine produces its therapeutic effects by inhibition of norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), and to a lesser extent, dopamine reuptake at the neuronal synapse. By inhibiting the reuptake of these neurotransmitters, sibutramine promotes a sense of satiety and decrease in appetite, thereby reducing food intake. Data from animal studies also suggest that sibutramine may also increase energy expenditure through thermogenic effects in both the basal and fed states, but this has not been confirmed in humans. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines.
Absorption Rapid absorption following oral administration. Absolute bioavailability is not known, but at least 77% of a single oral dose of sibutramine is absorbed.
Volume of distribution Not Available
Protein binding 97% (to human plasma proteins)
Metabolism

Hepatic
Route of elimination Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion.
Half life 1.1 hours
Clearance
  • Oral cl=1750 L/h [oral administration]
Toxicity Side effects include dry mouth, anorexia, insomnia, constipation and headache.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Abbott laboratories pharmaceutical products div
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Meridia 15 mg capsule 5.11 USD capsule
Meridia 10 mg capsule 4.02 USD capsule
Meridia 5 mg capsule 4.0 USD capsule
Patents
Country Patent Number Approved Expires
United States 5436272 1993-01-25 2013-01-25
Properties
State solid
Melting point 191-192 oC
Experimental Properties
Property Value Source
water solubility 2.9 mg/mL (in pH 5.2 water) PhysProp
logP 5.2 PhysProp
Predicted Properties
Property Value Source
water solubility 9.40e-04 g/l ALOGPS
logP 5.05 ALOGPS
logP 5.20 ChemAxon Molconvert
logS -5.47 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 1 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 3.24 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 83.92 ChemAxon Molconvert
polarizability 32.90 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Sharma B, Henderson DC: Sibutramine: current status as an anti-obesity drug and its future perspectives. Expert Opin Pharmacother. 2008 Aug;9(12):2161-73. Pubmed
  2. Tziomalos K, Krassas GE, Tzotzas T: The use of sibutramine in the management of obesity and related disorders: an update. Vasc Health Risk Manag. 2009;5(1):441-52. Pubmed
  3. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC: Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord. 1998 Aug;22 Suppl 1:S18-28; discussion S29. Pubmed
  4. Stock MJ: Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Int J Obes Relat Metab Disord. 1997 Mar;21 Suppl 1:S25-9. Pubmed
External Links
Resource Link
KEGG Drug D08513 Link_out
KEGG Compound C07247 Link_out
PubChem Compound 5210 Link_out
PubChem Substance 46507740 Link_out
ChemSpider 5021 Link_out
Therapeutic Targets Database DCL000881 Link_out
PharmGKB PA451344 Link_out
Drug Product Database 2243164 Link_out
RxList http://www.rxlist.com/cgi/generic/sibutramine.htm Link_out
Drugs.com http://www.drugs.com/cdi/sibutramine.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/mer1254.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Sibutramine Link_out
ATC Codes
  • A08AA10
AHFS Codes
  • 28:20.92
PDB Entries Not Available
FDA label show (133.7 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Sodium-dependent noradrenaline transporter

Pharmacological action: yes
Actions: inhibitor

Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals

Organism class: human
UniProt ID: P23975 Link_out
Gene: SLC6A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Heusser K, Engeli S, Tank J, Diedrich A, Wiesner S, Janke J, Luft FC, Jordan J: Sympathetic vasomotor tone determines blood pressure response to long-term sibutramine treatment. J Clin Endocrinol Metab. 2007 Apr;92(4):1560-3. Epub 2007 Feb 6. Pubmed
  3. Jordan J, Scholze J, Matiba B, Wirth A, Hauner H, Sharma AM: Influence of Sibutramine on blood pressure: evidence from placebo-controlled trials. Int J Obes (Lond). 2005 May;29(5):509-16. Pubmed
  4. Heusser K, Tank J, Diedrich A, Engeli S, Klaua S, Kruger N, Strauss A, Stoffels G, Luft FC, Jordan J: Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Clin Pharmacol Ther. 2006 May;79(5):500-8. Pubmed
  5. Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, Luft FC, Biaggioni I, Sharma AM, Jordan J: Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation. 2002 Nov 5;106(19):2459-65. Pubmed
  6. Birkenfeld AL, Schroeder C, Pischon T, Tank J, Luft FC, Sharma AM, Jordan J: Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese hypertensive patients—sibutramine and blood pressure. Clin Auton Res. 2005 Jun;15(3):200-6. Pubmed
  7. Tziomalos K, Krassas GE, Tzotzas T: The use of sibutramine in the management of obesity and related disorders: an update. Vasc Health Risk Manag. 2009;5(1):441-52. Pubmed
  8. Sharma B, Henderson DC: Sibutramine: current status as an anti-obesity drug and its future perspectives. Expert Opin Pharmacother. 2008 Aug;9(12):2161-73. Pubmed
  9. Gomis Barbara R: [Pharmacological treatment of obesity] Rev Med Univ Navarra. 2004 Apr-Jun;48(2):63-5. Pubmed
  10. Berke EM, Morden NE: Medical management of obesity. Am Fam Physician. 2000 Jul 15;62(2):419-26. Pubmed
  11. Krahn LE, Moore WR, Altchuler SI: Narcolepsy and obesity: remission of severe cataplexy with sibutramine. Sleep Med. 2001 Jan;2(1):63-65. Pubmed

2. Sodium-dependent serotonin transporter

Pharmacological action: yes
Actions: inhibitor

Terminates the action of serotonine by its high affinity sodium-dependent reuptake into presynaptic terminals

Organism class: human
UniProt ID: P31645 Link_out
Gene: SLC6A4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Vazquez Roque MI, Camilleri M, Clark MM, Tepoel DA, Jensen MD, Graszer KM, Kalsy SA, Burton DD, Baxter KL, Zinsmeister AR: Alteration of gastric functions and candidate genes associated with weight reduction in response to sibutramine. Clin Gastroenterol Hepatol. 2007 Jul;5(7):829-37. Epub 2007 Jun 4. Pubmed
  2. Heusser K, Engeli S, Tank J, Diedrich A, Wiesner S, Janke J, Luft FC, Jordan J: Sympathetic vasomotor tone determines blood pressure response to long-term sibutramine treatment. J Clin Endocrinol Metab. 2007 Apr;92(4):1560-3. Epub 2007 Feb 6. Pubmed
  3. Jordan J, Scholze J, Matiba B, Wirth A, Hauner H, Sharma AM: Influence of Sibutramine on blood pressure: evidence from placebo-controlled trials. Int J Obes (Lond). 2005 May;29(5):509-16. Pubmed
  4. Heusser K, Tank J, Diedrich A, Engeli S, Klaua S, Kruger N, Strauss A, Stoffels G, Luft FC, Jordan J: Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Clin Pharmacol Ther. 2006 May;79(5):500-8. Pubmed
  5. Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, Luft FC, Biaggioni I, Sharma AM, Jordan J: Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation. 2002 Nov 5;106(19):2459-65. Pubmed
  6. Birkenfeld AL, Schroeder C, Pischon T, Tank J, Luft FC, Sharma AM, Jordan J: Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese hypertensive patients—sibutramine and blood pressure. Clin Auton Res. 2005 Jun;15(3):200-6. Pubmed
  7. Tziomalos K, Krassas GE, Tzotzas T: The use of sibutramine in the management of obesity and related disorders: an update. Vasc Health Risk Manag. 2009;5(1):441-52. Pubmed
  8. Sharma B, Henderson DC: Sibutramine: current status as an anti-obesity drug and its future perspectives. Expert Opin Pharmacother. 2008 Aug;9(12):2161-73. Pubmed
  9. Gomis Barbara R: [Pharmacological treatment of obesity] Rev Med Univ Navarra. 2004 Apr-Jun;48(2):63-5. Pubmed
  10. Berke EM, Morden NE: Medical management of obesity. Am Fam Physician. 2000 Jul 15;62(2):419-26. Pubmed
  11. Krahn LE, Moore WR, Altchuler SI: Narcolepsy and obesity: remission of severe cataplexy with sibutramine. Sleep Med. 2001 Jan;2(1):63-65. Pubmed

3. Sodium-dependent dopamine transporter

Pharmacological action: yes
Actions: inhibitor

Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals

Organism class: human
UniProt ID: Q01959 Link_out
Gene: SLC6A3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Tziomalos K, Krassas GE, Tzotzas T: The use of sibutramine in the management of obesity and related disorders: an update. Vasc Health Risk Manag. 2009;5(1):441-52. Pubmed
  2. Gomis Barbara R: [Pharmacological treatment of obesity] Rev Med Univ Navarra. 2004 Apr-Jun;48(2):63-5. Pubmed
  3. Berke EM, Morden NE: Medical management of obesity. Am Fam Physician. 2000 Jul 15;62(2):419-26. Pubmed
  4. Nakagawa T, Ukai K, Ohyama T, Gomita Y, Okamura H: Effects of sibutramine on the central dopaminergic system in rodents. Neurotox Res. 2001 Jul;3(3):235-47. Pubmed
  5. Krahn LE, Moore WR, Altchuler SI: Narcolepsy and obesity: remission of severe cataplexy with sibutramine. Sleep Med. 2001 Jan;2(1):63-65. Pubmed
  6. Balcioglu A, Wurtman RJ: Sibutramine, a serotonin uptake inhibitor, increases dopamine concentrations in rat striatal and hypothalamic extracellular fluid. Neuropharmacology. 2000 Sep;39(12):2352-9. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Sharma B, Henderson DC: Sibutramine: current status as an anti-obesity drug and its future perspectives. Expert Opin Pharmacother. 2008 Aug;9(12):2161-73. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:46

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.