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药品详细

Sibutramine(西布曲明)

化学结构式图
中文名
西布曲明
英文名
Sibutramine
分子式
C17H26ClN
化学名
{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}dimethylamine
分子量
Average: 279.848
Monoisotopic: 279.175377544
CAS号
106650-56-0
ATC分类
A08A 未知
药物类型
small molecule
阶段
illicit, approved, withdrawn
商品名
同义名
基本介绍

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 In October 2010, Sibutramine was withdrawn from Canadian and U.S. markets due to concerns that the drug increases the risk of heart attack and stroke in patients with a history of heart disease.

生产厂家
  • Abbott laboratories pharmaceutical products div
封装厂家
参考
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
剂型
规格
化合物类型
Type small molecule
Classes
  • Phenethylamines
  • Amphetamines
Substructures
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Aliphatic and Aryl Amines
  • Cyclobutane and Derivatives
  • Phenethylamines
  • Aromatic compounds
  • Amphetamines
适应症
药理
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
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 191-192 °C Not Available
water solubility 2.9 mg/mL (in pH 5.2 water) Not Available
logP 5.2 Not Available
Predicted Properties
Property Value Source
water solubility 9.40e-04 g/l ALOGPS
logP 5.05 ALOGPS
logP 5.2 ChemAxon
logS -5.5 ALOGPS
pKa (strongest basic) 9.77 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 1 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 3.24 ChemAxon
rotatable bond count 5 ChemAxon
refractivity 83.92 ChemAxon
polarizability 32.9 ChemAxon
药物相互作用
Drug Interaction
Almotriptan Increased risk of CNS adverse effects
Amitriptyline Increased risk of CNS adverse effects
Amoxapine Increased risk of CNS adverse effects
Citalopram Risk of serotoninergic syndrome
Clomipramine Increased risk of CNS adverse effects
Cyclosporine Sibutramine increases the effect and toxicity of cyclosporine
Desipramine Increased risk of CNS adverse effects
Desvenlafaxine Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
Dextromethorphan Combination associated with possible serotoninergic syndrome
Dihydroergotamine Possible serotoninergic syndrome with this combination
Doxepin Increased risk of CNS adverse effects
Ergotamine Possible serotoninergic syndrome with this combination
Erythromycin Erythromycin increases the effect and toxicity of sibutramine
Escitalopram Risk of serotoninergic syndrome
Fluoxetine Risk of serotoninergic syndrome
Fluvoxamine Risk of serotoninergic syndrome
Frovatriptan Increased risk of CNS adverse effects
Imipramine Increased risk of CNS adverse effects
Isocarboxazid Possible serotoninergic syndrome with this combination
Ketoconazole Ketoconazole increases the levels and toxicity of sibutramine
Lithium Possible serotoninergic syndrome with this combination
Meperidine Possible serotoninergic syndrome
Methysergide Possible serotoninergic syndrome
Moclobemide Possible serotoninergic syndrome with this combination
Naratriptan Increased risk of CNS adverse effects
Nefazodone Risk of serotoninergic syndrome
Nortriptyline Increased risk of CNS adverse effects
Paroxetine Risk of serotoninergic syndrome
Phenelzine Possible serotoninergic syndrome with this combination
Rasagiline Possible serotoninergic syndrome with this combination
Telithromycin Telithromycin 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.
Tramadol Sibutramine may incrase the serotonergic effect of the Tramadol. Concomitant therapy should be avoided.
Tranylcypromine Increased risk of serotonin syndrome. Avoid concomitant therapy.
Trazodone Increased risk of serotonin syndrome. Avoid concomitant therapy.
Trimipramine Increased risk of serotonin syndrome. Concomitant therapy is contraindicated.
Venlafaxine Increased risk of serotonin syndrome. Concurrent therapy should be avoided.
Vilazodone Sibutramine may enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Avoid combination.
Voriconazole Voriconazole, 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.
Zolmitriptan Use of sibutramine, which inhibits serotonin reuptake, and zolmitriptan, a serotonin 5-HT1D receptor agonist, may cause serotonin syndrome. Concomitant therapy is contraindicated.
食物相互作用
Not Available

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