Pharmacokinetics
In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver. Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is around 2 hours. It is moderately bound to plasma proteins, especially albumin. However, the short disposition half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for systemic clearance and an intermediate volume of distribution. Despite its short half-life the pharmacodynamic action of a single dose persists for approximately 16 hours. The drug is almost completely metabolized in the liver; it is a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2. Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours. The main metabolites are the N-oxide Ro 12-5637 formed via morpholine N-oxidation and lactam derivative Ro 12-8095 formed via morpholine C-oxidation; active metabolites are found only in trace amounts. The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine). The main degradation pathway of moclobemide is oxidation. About 44 percent of the drug is lost due to the first pass effect through the liver. Age and renal function does not affect the pharmacokinetics of moclobemide. However, patients with significantly reduced liver function require dose reductions due to the significant slowing of metabolism of moclobemide. Food slows the absorption but does not affect the bioavailability of moclobemide.
Steady state concentrations are established after one week. It has been suggested that changes in dose should not be made with a gap of no less than a week. Moclobemide has good pentration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration.
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