CLINICAL PHARMACOKINETICS OF THE MONOAMINE OXIDASE-A INHIBITOR MOCLOBEMIDE

There has been a resurgence of interest in the use of monoamine oxidas e (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversi ble in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious presser effec ts. Furthermore, the current drugs are far more selective in their act ions as a result of the ability to affect either the MAO-A or the MAO- B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinica l pharmacological and toxicological profiles have been thoroughly defi ned. Moclobemide has a short disposition half-life and intermediate va lues for systemic clearance and volume of distribution; half-life incr eases somewhat with dose. The drug is completely metabolised by the li ver. Moclobemide is rapidly and completely absorbed following oral adm inistration in a variety of dosages and forms. The drug has a high int rinsic (apparent oral) clearance which results in a substantial hepati c first-pass effect and, while there is marked interindividual variati on, differences within an individual are small. A time- and dose-depen dence is observed with multiple oral administration: clearance decreas es with administration during the first week and thereafter remains co nstant. The exact mechanism of this effect is not known, but it may re flect inhibition of elimination by metabolites (the kinetics may alway s be described as being first-order). Moclobemide disposition is aot a ffected by renal disease, nor is there substantial alteration with adv anced age. Liver disease causes a dramatic reduction in clearance; dos age must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neona tes an exposed to only a very small dose of the drug. Moclobemide admi nistration results in a minimal interaction with exogenous amines (e.g . tyramine and presser amine drugs); the so-called 'cheese effect' is therefore of little concern. As a result, the drug has an excellent to lerability profile both within the therapeutic dose range and in overd ose (no deaths have been attributed to moclobemide intoxication per se ). Cimetidine inhibits the elimination of moclobemide. Moclobemide app ears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemid e indicates only mild and transient effects at a relatively low rate o f occurrence.