Description

Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor (SNRI) similar to certain antidepressants.

Sibutramine has been used to produce appetite suppression for the purpose of attaining weight loss in the treatment of patients with obesity.

Sibutramine is a serotonin–norepinephrine reuptake inhibitor (SNRI) that, in humans, reduces the reuptake of norepinephrine (by ~73%), serotonin (by ~54%), and dopamine (by ~16%), thereby increasing the levels of these substances in synaptic clefts and helping enhance satiety; the serotonergic action, in particular, is thought to influence appetite. Older anorectic agents such as amphetamine and fenfluramine force the release of these neurotransmitters rather than affecting their reuptake.

Sibutramine’s mechanism of action is similar to tricyclic antidepressants, and it has demonstrated antidepressant effects in animal models of depression. It was approved by the U.S. Food and Drug Administration (FDA) in November 1997 for the treatment of obesity.

Sibutramine is reported to be a prodrug to two active metabolites, desmethylsibutramine (M1; BTS-54354) and didesmethylsibutramine (M2; BTS-54505), with much greater potency as monoamine reuptake inhibitors. Further studies have indicated that the (R)-enantiomers of each metabolite exert significantly stronger anorectic effects than the (S)-enantiomers.

Unlike other serotonergic appetite suppressants like fenfluramine, sibutramine and its metabolites have only low and likely inconsequential affinity for the 5-HT_2B receptor.

Sibutramine is well absorbed from the gastrointestinal tract (77%), but undergoes considerable first-pass metabolism, reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a half-life of 1 hour. Sibutramine is metabolized by cytochrome P450 isozyme CYP3A4 into two pharmacologically active primary and secondary amines (called active metabolites 1 and 2) with half-lives of 14 and 16 hours, respectively. Peak plasma concentrations of active metabolites 1 and 2 are reached after three to four hours. The following metabolic pathway mainly results in two inactive conjugated and hydroxylated metabolites (called metabolites 5 and 6). Metabolites 5 and 6 are mainly excreted in the urine.

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