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Identification
NameSibutramine
Accession NumberDB01105  (APRD00456)
TypeSmall Molecule
GroupsApproved, Illicit, Investigational, Withdrawn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 In October 2010, Sibutramine was withdrawn from Canadian and U.S. markets due to concerns that the drug increases the risk of heart attack and stroke in patients with a history of heart disease.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
Synonyms
Butramin
Sibutramina
Sibutraminum
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Meridiacapsule10 mgoralAbbott Laboratories, Limited2001-02-282010-10-12Canada
Meridiacapsule15 mgoralAbbott Laboratories, Limited2001-02-282010-10-12Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-sibutraminecapsule10 mgoralApotex Inc2009-11-232010-10-12Canada
Apo-sibutraminecapsule15 mgoralApotex Inc2009-11-232010-10-12Canada
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
ButraminNot Available
MedariaNot Available
ReductilNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Sibutramine hydrochloride
ThumbNot applicableDBSALT001451
Sibutramine hydrochloride monohydrate
ThumbNot applicableDBSALT001132
Categories
UNIIWV5EC51866
CAS number106650-56-0
WeightAverage: 279.848
Monoisotopic: 279.175377544
Chemical FormulaC17H26ClN
InChI KeyInChIKey=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
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as chlorobenzenes. These are compounds containing one or more chlorine atoms attached to a benzene moiety.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassHalobenzenes
Direct ParentChlorobenzenes
Alternative Parents
Substituents
  • Aralkylamine
  • Chlorobenzene
  • Aryl halide
  • Aryl chloride
  • Tertiary aliphatic amine
  • Tertiary amine
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of obesity.
PharmacodynamicsSibutramine 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 actionSibutramine 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.
Related Articles
AbsorptionRapid absorption following oral administration. Absolute bioavailability is not known, but at least 77% of a single oral dose of sibutramine is absorbed.
Volume of distributionNot Available
Protein binding97% (to human plasma proteins)
Metabolism

Hepatic

Route of eliminationSibutramine 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 life1.1 hours
Clearance
  • Oral cl=1750 L/h [oral administration]
ToxicitySide effects include dry mouth, anorexia, insomnia, constipation and headache.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9948
Blood Brain Barrier+0.9667
Caco-2 permeable+0.6584
P-glycoprotein substrateNon-substrate0.5148
P-glycoprotein inhibitor INon-inhibitor0.718
P-glycoprotein inhibitor IIInhibitor0.5071
Renal organic cation transporterNon-inhibitor0.5805
CYP450 2C9 substrateNon-substrate0.8056
CYP450 2D6 substrateNon-substrate0.9115
CYP450 3A4 substrateSubstrate0.6969
CYP450 1A2 substrateNon-inhibitor0.7059
CYP450 2C9 inhibitorNon-inhibitor0.9205
CYP450 2D6 inhibitorNon-inhibitor0.754
CYP450 2C19 inhibitorNon-inhibitor0.7041
CYP450 3A4 inhibitorNon-inhibitor0.969
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8292
Ames testNon AMES toxic0.837
CarcinogenicityNon-carcinogens0.5808
BiodegradationNot ready biodegradable0.9903
Rat acute toxicity2.9056 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9065
hERG inhibition (predictor II)Inhibitor0.769
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral10 mg
Capsuleoral15 mg
Prices
Unit descriptionCostUnit
Meridia 15 mg capsule5.11USD capsule
Meridia 10 mg capsule4.02USD capsule
Meridia 5 mg capsule4.0USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5436272 No1993-01-252013-01-25Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point191-192 °CNot Available
water solubility2.9 mg/mL (in pH 5.2 water)Not Available
logP5.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00094 mg/mLALOGPS
logP5.05ALOGPS
logP5.2ChemAxon
logS-5.5ALOGPS
pKa (Strongest Basic)9.77ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area3.24 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity83.92 m3·mol-1ChemAxon
Polarizability32.9 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

Chris Senanayake, “Methods of preparing didesmethylsibutramine and other sibutramine derivatives.” U.S. Patent US20020183554, issued December 05, 2002.

US20020183554
General 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. doi: 10.1517/14656566.9.12.2161 . [PubMed:18671470 ]
  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:19475780 ]
  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:9758240 ]
  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:9130038 ]
External Links
ATC CodesA08AA10
AHFS Codes
  • 28:20.92
PDB EntriesNot Available
FDA labelDownload (134 KB)
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Serotonin:sodium symporter activity
Specific Function:
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin an...
Gene Name:
SLC6A4
Uniprot ID:
P31645
Molecular Weight:
70324.165 Da
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:17544870 ]
  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:17284621 ]
  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:15685250 ]
  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:16678551 ]
  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:12417543 ]
  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:15944869 ]
  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:19475780 ]
  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. doi: 10.1517/14656566.9.12.2161 . [PubMed:18671470 ]
  9. Gomis Barbara R: [Pharmacological treatment of obesity]. Rev Med Univ Navarra. 2004 Apr-Jun;48(2):63-5. [PubMed:15382615 ]
  10. Berke EM, Morden NE: Medical management of obesity. Am Fam Physician. 2000 Jul 15;62(2):419-26. [PubMed:10929704 ]
  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:11152984 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Norepinephrine:sodium symporter activity
Specific Function:
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A2
Uniprot ID:
P23975
Molecular Weight:
69331.42 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  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:17284621 ]
  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:15685250 ]
  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:16678551 ]
  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:12417543 ]
  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:15944869 ]
  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:19475780 ]
  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. doi: 10.1517/14656566.9.12.2161 . [PubMed:18671470 ]
  9. Gomis Barbara R: [Pharmacological treatment of obesity]. Rev Med Univ Navarra. 2004 Apr-Jun;48(2):63-5. [PubMed:15382615 ]
  10. Berke EM, Morden NE: Medical management of obesity. Am Fam Physician. 2000 Jul 15;62(2):419-26. [PubMed:10929704 ]
  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:11152984 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Monoamine transmembrane transporter activity
Specific Function:
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A3
Uniprot ID:
Q01959
Molecular Weight:
68494.255 Da
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:19475780 ]
  2. Gomis Barbara R: [Pharmacological treatment of obesity]. Rev Med Univ Navarra. 2004 Apr-Jun;48(2):63-5. [PubMed:15382615 ]
  3. Berke EM, Morden NE: Medical management of obesity. Am Fam Physician. 2000 Jul 15;62(2):419-26. [PubMed:10929704 ]
  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:15111248 ]
  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:11152984 ]
  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:10974319 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
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 xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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. doi: 10.1517/14656566.9.12.2161 . [PubMed:18671470 ]
  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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23