Moclobemide

Moclobemide is an antidepressant which affects the monoaminergic cerebral neurotransmitter system by means of a reversible inhibition of monoamine oxidase preferentially of type A (RIMA). The metabolism of noradrenaline, dopamine and serotonin (5-HT) is decreased by this effect, and this leads to increased extracellular concentrations of these neuronal transmitters.

As a result of its elevating effect on mood and psychomotor activity, moclobemide relieves symptoms such as dysphoria, exhaustion, lack of drive and inability to concentrate.

These effects most often appear within the first week of therapy. Moclobemide also relieves symptoms related to social phobia.

Though moclobemide has no sedative properties, it improves the quality of sleep in most depressive patients within days. Moclobemide does not impair alertness.

Short-term and long-term animal studies indicate low toxicity. No cardiac toxicity has been observed.

Absorption

After oral administration, moclobemide is completely absorbed from the gastrointestinal tract into the portal blood. Peak plasma concentrations of the drug are usually reached within one hour of dosage. A hepatic first-pass effect reduces the systemically available dose fraction (bioavailability F). This reduction is more pronounced after single (F: 60%) than after multiple (F: 80%) doses. After multiple dosing, plasma concentrations of moclobemide increase over the first week of therapy and remain stable thereafter. When the daily dose is increased, there is a more than proportional increase in steady-state concentrations.

Distribution

Due to its lipophilic nature, moclobemide is extensively distributed in the body. The volume of distribution (V_ss) is about 1.0 l/kg. Binding of the drug to plasma proteins, mainly albumin, is low (50%).

Metabolism

The drug is almost entirely metabolised before its elimination from the body. Metabolism occurs largely via oxidative reactions on the morpholine moiety of the molecule. Degradation products with pharmacological activity are present in the systemic circulation in man at very low concentrations only. The major metabolites present in plasma are a lactam derivative and an N-oxide derivative. Moclobemide has been shown to be metabolised in part by the polymorphic isoenzymes CYP2C19 and CYP2D6. Thus, in genetically or drug-induced (via metabolic inhibitors) poor metabolisers, metabolism of the drug may be affected. Two studies conducted to investigate the magnitude of these effects suggested that, due to the presence of multiple alternative metabolic pathways, in general they are of no clinical significance and should not necessitate dosage modification.

Elimination

Moclobemide is rapidly eliminated by metabolic processes. Total clearance is approximately 20-50 1/hour. The mean elimination half-life during multiple dosing (300mg b.i.d) is approximately 3 hours and generally ranges from 2–4 hours in most patients. Less than 1% of a dose is excreted renally in unchanged form. The metabolites formed are eliminated renally. Insignificant amounts are excreted in human breast milk.

Pharmacokinetics in special populations

Elderly

Absorption and disposition parameters are unchanged in the elderly.

Patients with renal impairment

Renal disease does not alter the elimination characteristics of moclobemide.

Patients with hepatic impairment

In advanced liver insufficiency, the metabolism of moclobemide is reduced.

Preclinical data, based on conventional studies of safety pharmacology, single- and repeat-dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction did not reveal special hazards for humans associated with moclobemide.