Pharmacodynamics +<unk>  (and metabolites) Compound<unk>  298–2,800 350–5,451 943–1,200 Desmethylsibutramine 15 20 49 (R)-Desmethylsibutramine 44 4 12 (S)-Desmethylsibutramine 9,200 870 180 Didesmethylsibutramine 20 15 45 (R)-Didesmethylsibutramine 140 13 8.9 (S)-Didesmethylsibutramine 4,300 62 12 Values are Ki (nM).<unk>  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. Despite having a mechanism of action similar to tricyclic antidepressants,<unk>  has failed to demonstrate antidepressant properties in animal studies. It was approved by the U.S. Food and Drug Administration (FDA) in November 1997 for the treatment of obesity.<unk>  is reported to be a prodrug to two active metabolites, desmethylsibutramine (M1; BTS-54354) and didesmethylsibutramine (M2; BTS-54505), with much greater potency as MRIs. Unlike other serotonergic appetite suppressants like fenfluramine,<unk>  and its metabolites have only low and likely inconsequential affinity for the 5-HT2B receptor. Pharmacokinetics<unk>  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.<unk>  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.
Sibutramine
Lofepramine
Quinupramine
Mitapivat
Metapramine
Nyasol
Tasimelteon
Pipotiazine