Contribution of flavin-containing monooxygenase and cytochrome P450 to imipramine N-oxidation in rat hepatic microsomes.
Enzymatic formation of desipramine (DMI) and imipramine N-oxide (IMINO) was kinetically characterized in rat liver microsomes at pH 8.5 and 7.5. The formation of IMINO was quickly suppressed by the preincubation of microsomes at 37 degrees C at pH 8.5, but the suppression was comparatively gentle at pH 7.5. In kinetic studies, the formation of DMI was monophasic at the two pH points, and a substrate inhibition was observed at pH 8.5, but not at pH 7.5. In contrast, the formation of IMINO was biphasic at both pH points, Le., the summation of a low-Km phase and a high-Km phase. Methimazole (MZ), an inhibitor of flavin-containing monooxygenase (FMO), markedly suppressed the low-Km phase of IMINO formation at both pH points. MZ also suppressed DMI formation at pH 8.5, but it elevated DMI formation at pH 7.5. SKF 525-A, an inhibitor of cytochrome P450 (CYP), markedly suppressed DMI formation at both pH points. The inhibitor suppressed IMINO formation in the high-Km phase of the biphasic kinetics at both pH points, whereas it stimulated the activity of the low-Km phase at pH 7.5. These results suggest that CYP enzyme(s) are mainly responsible for DMI formation at pH 8.5 and 7.5, and FMO enzyme(s) also are involved in IMI N-demethylation at a higher pH range in rat liver microsomes, at least in part. In the formation of IMINO, FMO is a major enzyme at both pH points, and CYP may also contribute to the N-oxide formation to some extent at pH 8.5.
Narimatsu
S
S
Department of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Japan.
Yamamoto
S
S
Kato
R
R
Masubuchi
Y
Y
Horie
T
T
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D006035:Glycyrrhiza; D006863:Hydrogen-Ion Concentration; D007099:Imipramine / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000502:physiology*; D029596:Paeonia; D051381:Rats; D017208:Rats, Wistar
D000929:Antidepressive Agents, Tricyclic; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; C038462:shakuyaku-kanzoh-toh; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D007099:Imipramine