Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats.
The aim of this study was to investigate imipramine-induced alterations of cytochrome P-450 and to determine whether prolonged concomitant administration of imipramine and lithium results in a pharmacokinetic interaction. Male Wistar rats received imipramine (10 mg/kg i.p.) at 12 h intervals or lithium chloride (100 mg/kg in drinking water) or they were treated with the combination of these drugs for 2 weeks. The long term treatment with imipramine produced a very complex alteration of cytochrome P-450: imipramine increased the level of the cytochrome, but it decreased the rate of its own aromatic hydroxylation in position 2. The rate of N-demethylation in the side chain was not changed. Consequently, in the case of both hydroxylation and demethylation, calculated molecular activities were decreased to 48% and 70% respectively. This differential change in activities corresponded well to the observed decrease of absorption in difference spectra (type I) produced in microsomes by imipramine. Carbamazepine-induced type I difference spectra were also decreased by imipramine pretreatment, but to a lesser extent. In contrast, hexobarbital type I binding was increased by imipramine treatment while type II difference spectra produced by metyrapone were not affected. The preliminary SDS-PAGE analysis of cytochrome P-450 isoenzymes of control and imipramine treated rats showed that the investigated antidepressant markedly intensified a protein band at 50.11 kD while bands at 51.28 kD, 56.20 kD and 56.88 kD were less intensive. These results indicate that the alteration of cytochrome P-450 by imipramine treatment is not only of quantitative but also of qualitative character. Lithium alone given to rats affected neither the concentration of cytochrome P-450 in microsomal protein nor the rate of imipramine metabolism in vitro. Lithium given jointly with imipramine reduced imipramine-induced elevation of cytochrome P-450.(ABSTRACT TRUNCATED AT 250 WORDS)
Daniel
W
W
Department of Pharmacology and Toxicology, University of Marburg, Medical School, Federal Republic of Germany.
Netter
K J
KJ
D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003891:Desipramine / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D004591:Electrophoresis, Polyacrylamide Gel; D006591:Hexobarbital / Q000494:pharmacology; D007099:Imipramine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008094:Lithium / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D007527:Isoenzymes; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; D008094:Lithium; D006591:Hexobarbital; D007099:Imipramine; D003891:Desipramine; D008797:Metyrapone