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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Groupsapproved, illicit, investigational, withdrawn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 In October 2010, Sibutramine was withdrawn from Canadian and U.S. markets due to concerns that the drug increases the risk of heart attack and stroke in patients with a history of heart disease.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
SynonymLanguageCode
SibutraminaSpanishNot Available
SibutraminumLatinNot Available
SaltsNot Available
Brand names
NameCompany
ButraminNot Available
MedariaNot Available
MeridiaAbbott Laboratories, Inc.
ReductilNot Available
Brand mixturesNot Available
Categories
CAS number106650-56-0
WeightAverage: 279.848
Monoisotopic: 279.175377544
Chemical FormulaC17H26ClN
InChI KeyUNAANXDKBXWMLN-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassHalobenzenes
Direct parentChlorobenzenes
Alternative parentsAryl Chlorides; Tertiary Amines; Polyamines; Organochlorides
Substituentsaryl chloride; aryl halide; tertiary amine; polyamine; organochloride; organohalogen; amine; organonitrogen compound
Classification descriptionThis compound belongs to the chlorobenzenes. These are compounds containing one or more chlorine atoms attached to a benzene moiety.
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.
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
Property Value Probability
Human Intestinal Absorption + 0.9948
Blood Brain Barrier + 0.9667
Caco-2 permeable + 0.6584
P-glycoprotein substrate Non-substrate 0.5148
P-glycoprotein inhibitor I Non-inhibitor 0.718
P-glycoprotein inhibitor II Inhibitor 0.5071
Renal organic cation transporter Non-inhibitor 0.5805
CYP450 2C9 substrate Non-substrate 0.8056
CYP450 2D6 substrate Non-substrate 0.9115
CYP450 3A4 substrate Substrate 0.6969
CYP450 1A2 substrate Non-inhibitor 0.7059
CYP450 2C9 substrate Non-inhibitor 0.9205
CYP450 2D6 substrate Non-inhibitor 0.754
CYP450 2C19 substrate Non-inhibitor 0.7041
CYP450 3A4 substrate Non-inhibitor 0.969
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8292
Ames test Non AMES toxic 0.837
Carcinogenicity Non-carcinogens 0.5808
Biodegradation Not ready biodegradable 0.9903
Rat acute toxicity 2.9056 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9065
hERG inhibition (predictor II) Inhibitor 0.769
Pharmacoeconomics
Manufacturers
  • Abbott laboratories pharmaceutical products div
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Meridia 15 mg capsule5.11USDcapsule
Meridia 10 mg capsule4.02USDcapsule
Meridia 5 mg capsule4.0USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States54362721993-01-252013-01-25
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 solubility9.40e-04 g/lALOGPS
logP5.05ALOGPS
logP5.2ChemAxon
logS-5.5ALOGPS
pKa (strongest basic)9.77ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count1ChemAxon
hydrogen donor count0ChemAxon
polar surface area3.24ChemAxon
rotatable bond count5ChemAxon
refractivity83.92ChemAxon
polarizability32.9ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

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

US20020183554
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
ResourceLink
KEGG DrugD08513
KEGG CompoundC07247
PubChem Compound5210
PubChem Substance46507740
ChemSpider5021
Therapeutic Targets DatabaseDCL000881
PharmGKBPA451344
IUPHAR2586
Guide to Pharmacology2586
Drug Product Database2243164
RxListhttp://www.rxlist.com/cgi/generic/sibutramine.htm
Drugs.comhttp://www.drugs.com/cdi/sibutramine.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/mer1254.shtml
WikipediaSibutramine
ATC CodesA08AA10
AHFS Codes
  • 28:20.92
PDB EntriesNot Available
FDA labelshow(134 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AlmotriptanIncreased risk of CNS adverse effects
AmitriptylineIncreased risk of CNS adverse effects
AmoxapineIncreased risk of CNS adverse effects
CitalopramRisk of serotoninergic syndrome
ClomipramineIncreased risk of CNS adverse effects
CyclosporineSibutramine increases the effect and toxicity of cyclosporine
DesipramineIncreased risk of CNS adverse effects
DesvenlafaxineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
DextromethorphanCombination associated with possible serotoninergic syndrome
DihydroergotaminePossible serotoninergic syndrome with this combination
DoxepinIncreased risk of CNS adverse effects
ErgotaminePossible serotoninergic syndrome with this combination
ErythromycinErythromycin increases the effect and toxicity of sibutramine
EscitalopramRisk of serotoninergic syndrome
FluoxetineRisk of serotoninergic syndrome
FluvoxamineRisk of serotoninergic syndrome
FrovatriptanIncreased risk of CNS adverse effects
ImipramineIncreased risk of CNS adverse effects
IsocarboxazidPossible serotoninergic syndrome with this combination
KetoconazoleKetoconazole increases the levels and toxicity of sibutramine
LithiumPossible serotoninergic syndrome with this combination
MethysergidePossible serotoninergic syndrome
MoclobemidePossible serotoninergic syndrome with this combination
NaratriptanIncreased risk of CNS adverse effects
NefazodoneRisk of serotoninergic syndrome
NortriptylineIncreased risk of CNS adverse effects
ParoxetineRisk of serotoninergic syndrome
PethidinePossible serotoninergic syndrome
PhenelzinePossible serotoninergic syndrome with this combination
RasagilinePossible serotoninergic syndrome with this combination
TelithromycinTelithromycin may reduce clearance of Sibutramine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Sibutramine if Telithromycin is initiated, discontinued or dose changed.
TramadolSibutramine may incrase the serotonergic effect of the Tramadol. Concomitant therapy should be avoided.
TranylcypromineIncreased risk of serotonin syndrome. Avoid concomitant therapy.
TrazodoneIncreased risk of serotonin syndrome. Avoid concomitant therapy.
TrimipramineIncreased risk of serotonin syndrome. Concomitant therapy is contraindicated.
VenlafaxineIncreased risk of serotonin syndrome. Concurrent therapy should be avoided.
VilazodoneSibutramine may enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Avoid combination.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of sibutramine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of sibutramine if voriconazole is initiated, discontinued or dose changed.
ZolmitriptanUse of sibutramine, which inhibits serotonin reuptake, and zolmitriptan, a serotonin 5-HT1D receptor agonist, may cause serotonin syndrome. Concomitant therapy is contraindicated.
Food InteractionsNot Available

Targets

1. Sodium-dependent noradrenaline transporter

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium-dependent noradrenaline transporter P23975 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium-dependent serotonin transporter P31645 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium-dependent dopamine transporter Q01959 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13