Mode of Action

Sibutramine produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Sibutramine and its major pharmacologically active metabolites (M₁ and M₂) do not act via release of monoamines.

Pharmacodynamics

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 (5-hydroxytryptamine, 5-HT) 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.

Potencies of Sibutramine, M₁ and M₂ as In Vitro Inhibitors of Monoamine Reuptake in Human Brain Potency to Inhibit Monoamine Reuptake (K_i;nM)

A study using plasma samples taken from sibutramine-treated volunteers showed monoamine reuptake inhibition of norepinephrine > serotonin > dopamine; maximum inhibitions were norepinephrine = 73%, serotonin = 54% and dopamine = 16%.

Sibutramine and its metabolites (M₁ and M₂) are not serotonin, norepinephrine or dopamine releasing agents. Following chronic administration of sibutramine to rats, no depletion of brain monoamines has been observed.

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-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C), norepinephrine (β, β1, β3, α1 and α2), dopamine (D₁ and D₂), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

Pharmacokinetics

Absorption

Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 h) to form the pharmacologically active mono- and di-desmethyl metabolites M₁ and M₂. Peak plasma concentrations of M₁ and M₂ are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined.

Distribution

Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. In vitro, sibutramine, M₁ and M₂ are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses.

Metabolism

Bookmark this page: