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.
Gram
L F
LF
Department of Clinical Pharmacology, Odense University, Denmark.
Guentert
T W
TW
Grange
S
S
Vistisen
K
K
Brøsen
K
K
D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001549:Benzamides / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D020912:Moclobemide; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011446:Prospective Studies; D012016:Reference Values
D000928:Antidepressive Agents; D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D020912:Moclobemide