MOCLOBEMIDE, A SUBSTRATE OF CYP2C19 AND AN INHIBITOR OF CYP2C19, CYP2D6, AND CYP1A2 - A PANEL STUDY

The reversible monoamine oxidase A inhibitor moclobemide was given in single (300 mg) and multiple doses (600 mg/day) to 11 male and four female healthy volunteers (age range, 23 to 27) who were either poor metabolizers of S-mephenytoin (n = 7) or extensive metabolizers of S-mephenytoin (n = 8), All were extensive metabolizers of sparteine, poor metabolizers of S-mephenytoin had lower moclobemide clearance values (median, single dose: 16.1 versus 43.2 L . hr(-1); steady state: 13.4 versus 22.1 L . hr(-1)) and longer moclobemide half-life values (median, single dose: 4.0 versus 1.8 hours; steady state: 5.1 versus 2.7 hours) than extensive metabolizers of S-mephenytoin, The plasma levels of a metabolite formed by C-hydroxylation (Ro 12-8095) were lower in poor metabolizers of S-mephenytoin than in extensive metabolizers of S-mephenytoin, Moclobemide thus partially undergoes oxidative metabolism by way of the polymorphic CYP2C19, A combined mephenytoin, sparteine, and caffeine test performed before, during, and after multiple dosing of moclobemide showed changes in the metabolic indexes compatible with a reversible inhibition of oxidation by way of the corresponding CYP enzymes-CYP2C19, CYP2D6, and CYP1A2-during moclobemide treatment.