Inhibitors of imipramine metabolism by human liver microsomes.
1. The aromatic 2-hydroxylation of imipramine was studied in microsomes from three human livers. The kinetics were best described by a biphasic enzyme model. The estimated values of Vmax and Km for the high affinity site ranged from 3.2 to 5.7 nmol mg-1 h-1 and from 25 to 31 microM, respectively. 2. Quinidine was a potent inhibitor of the high affinity site for the 2-hydroxylation of imipramine in microsomes from all three human livers, with apparent Ki-values ranging from 9 to 92 nM. This finding strongly suggests that the high affinity enzyme is CYP2D6, the source of the sparteine/debrisoquine oxidation polymorphism. 3. The selective serotonin reuptake inhibitors (SSRI), paroxetine, fluoxetine and norfluoxetine were potent inhibitors of the high affinity site having apparent Ki-values of 0.36, 0.92 and 0.33 microM, respectively. Three other SSRIs, citalopram, desmethylcitalopram and fluvoxamine, were less potent inhibitors of CYP2D6, with apparent Ki-values of 19, 1.3 and 3.9 microM, respectively. 4. Among 20 drugs screened, fluvoxamine was the only potent inhibitor of the N-demethylation of imipramine, with a Ki-value of 0.14 microM. 5. Neither mephenytoin, citalopram, diazepam, omeprazole or proguanil showed any inhibition of the N-demethylation of imipramine and the role of the S-mephenytoin hydroxylase for this oxidative pathway could not be confirmed.
Skjelbo
E
E
Department of Clinical Pharmacology, Odense University, Denmark.
Brøsen
K
K
D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D016666:Fluvoxamine / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D007099:Imipramine / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011110:Polymorphism, Genetic; D011802:Quinidine / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D016666:Fluvoxamine; D007099:Imipramine; D006899:Mixed Function Oxygenases; D011802:Quinidine; D017367:Selective Serotonin Reuptake Inhibitors