Moclobemide

🧬 Receptor activity

Target	Action	Affinity	Source
Amine oxidase [flavin-containing] A	—	Ki 0.5 nM	CHEMBL
Sigma non-opioid intracellular receptor 1	—	Ki 100 nM	CHEMBL
Sigma intracellular receptor 2	—	Ki 200 nM	CHEMBL
Amine oxidase [flavin-containing] B	—	Ki 1080 nM	CHEMBL
Unchecked	—	Ki 2250 nM	CHEMBL

Mechanism of action

The mechanism of action of moclobemide involves the selective, reversible inhibition of MAO-A. This inhibition leads to a decrease in the metabolism and destruction of monoamines in the neurotransmitters. This results in an increase in the monoamines, relieving depressive symptoms.
The exact mechanism of antidepressant effect is unknown; however, it is established that the activity of the enzyme monoamine oxidase (MAO) is inhibited. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters, such as norepinephrine and dopamine. Moclobemide, as a selective MAO inhibitor, preferentially inhibits monoamine oxidase-A (MAO-A) and, to a lesser extent, monoamine oxidase-B (MAO-B) (approximately 80% inhibition of MAO-A and 20% to 30% inhibition of MAO-B, 300 mg). Reduced MAO activity results in an increased concentration of serotonin and catecholamine neurotransmitters in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. This increased availability of one or more monoamines has been thought to be the basis for the antidepressant activity of MAO inhibitors. MAO-A inhibition by moclobemide is short-acting (maximum 24 hours) and reversible (transient binding to MAO-A). In contrast, some other MAO inhibitors (phenelzine, tranylcypromine) are non-selective, long-acting, and irreversible in their binding to MAO-A and MAO-B.

Pharmacodynamics

A selective, reversible inhibitor of monoamine oxidase (MAO) which increases the. Besides its presence in sympathetic nerves, there is an abundant evidence that MAO-A is localized in noradrenergic neurons in the locus coeruleus and MAO-B is closely associated with serotonergic neurons of the raphe nucleus.

Pharmacokinetics

Half-life

1-2 hours (4 hours in cirrhotic patients); metabolites are renally excreted
Elimination: 1.5 hours (4 hours in cirrhotic patients).

Absorption

Well absorbed from the gastrointestinal tract (> 95%). The presence of food reduces the rate but not the extent of absorption. Hepatic first-pass metabolism reduces bioavailability to about 56% following administration of one dose, but increases to 90% with steady-state dosing as a result of saturation of the first pass effect. Peak plasma concentrations are reached within 0.3 - 1 hours following oral administration with a terminal half-life of 1.6h.
Moclobemide is almost completely renally excreted.
1-1.5 L/Kg
Clearance of 30-78 L/h, mainly excreted in urine.
Moclobemide is readily absorbed (>95%) through the gastrointestinal tract. Within 1 to 2 hours of oral use, a peak plasma level of about 1 ug/mL is reached. It is protein bound to the extent of 50%.
Small quantities of moclobemide are distributed into human breast milk.

Metabolism

Moclobemide is almost completely metabolized in the liver by Cytochrome P450 2C19 and 2D6. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6.
The role of mephenytoin oxidation polymorphism in the metabolism of moclobemide was studied in 15 healthy subjects (ages 23-27 yr), including 7 poor metabolizers and 8 extensive metabolizers of S-mephenytoin, who received a single dose of 300 mg moclobemide and multiple doses of 600 mg/day moclobemide. Poor metabolizers of S-mephenytoin had lower moclobemide clearance (median single dose 16.1 vs 43.2 L/hr) and longer half-life (median single dose 4 vs 1.8 hr) compared with extensive metabolizers. Plasma levels of a metabolite formed by C-hydroxylation were lower in poor metabolizers. Moclobemide thus partially underwent oxidative metabolism via polymorphic CYP2C19. Changes in metabolic indexes were compatible with reversible inhibition of oxidation by way of CYP2C19, CYP2D6, and CYP1A2. It was concluded that there is a cosegregation between moclobemide clearance and mephenytoin oxidation polymorphism.
Moclobemide appears to be eliminated (after first-pass hepatic metabolism) by first-order kinetics, resulting in urinary excretion of the monoamine metabolites homovanillic acid (HAV), dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxy-phenyl glycol (DOPEG), and 5-hydroxyindoleacetic acid (5-HIAA).
Moclobemide is almost completely metabolized in the liver by Cytochrome P450 2C19 and 2D6.
Half Life: 1-2 hours (4 hours in cirrhotic patients); metabolites are renally excreted

Protein binding

Approximately 50% (primarily to albumin)