| 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. |
