In vitro metabolism of imipramine by brain microsomes: effects of inhibitors and exogenous cytochrome P450 reductase.
The metabolism of imipramine in the brains of rats was analyzed to study the activity of cytochrome P450 in brain microsomes. Brain microsomes were capable of metabolizing imipramine to both hydroxylated and N-demethylated products. The use of selective inhibitors of different cytochromes P450 effected varying changes in the metabolic profiles of formed metabolites consistent with the involvement of several P450 forms in imipramine metabolism. Quinidine inhibited the hydroxylation of imipramine competitively by 60% and 98% at concentrations of 10 microM and 100 microM, respectively. Ketoconazole and 7,8-benzoflavone at a concentration of 100 microM inhibited N-demethylation of imipramine by 75% and 30%, respectively, with a lower effect on imipramine hydroxylation. Results from studies on the incorporation of cytochrome P450 reductase into the brain microsomal system reveal a reductase concentration-dependent increase in imipramine metabolism and suggest that the reductase level in brain is an important factor for the study of catalytic activities in brain microsomal systems.
Sequeira
D J
DJ
Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston 77225, USA.
Strobel
H W
HW
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D007099:Imipramine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000494:pharmacology*; D009251:NADPH-Ferrihemoprotein Reductase; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009994:Osmolar Concentration; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001571:Benzoflavones; D009419:Nerve Tissue Proteins; C011512:alpha-naphthoflavone; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; D011802:Quinidine; D007099:Imipramine; D007654:Ketoconazole