Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats.

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Masubuchi Y, Takahashii C, Fujio N, Horie T, Suzuki T, Imaoka S, Funae Y, Narimatsu S

Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats.

Drug Metab Dispos. 1995 Sep;23(9):999-1003.

PubMed ID

8565792 [ View in PubMed

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Abstract

Repetitive oral administration of imipramine (100 mg/kg/day for 5 days) caused a decrease in rat liver microsomal debrisoquine 4-hydroxylase activity, a characteristic reaction catalyzed by cytochrome P450 (CYP) 2D1. Other CYP2D-dependent reactions (such as bunitrolol 4-hydroxylation, lidocaine 3-hydroxylation, and propranolol 4-, 5- and 7-hydroxylations) were also impaired by the treatment, but not those catalyzed by other CYP isozymes. Imipramine pretreatment did not change the immunochemically determined content of the CYP2D protein, suggesting that CYP2D is inactivated. Imipramine pretreatment also resulted in an increase in total CYP content and in formation of a ferrous CYP metabolic intermediate (MI)-complex absorbing at 454 nm. Although the total CYP content was increased by the treatment of these microsomes with ferricyanide to dissociate the MI-complex, the CYP2D-dependent activities were not restored, suggesting that the MI-complex was not the primary cause of CYP2D inhibition. This pretreatment regimen caused marked increases in immunochemically determined levels of CYP2A1, CYP2B1, CYP2B2, CYP2C6, and CYP3A2, and in the activities of 2 alpha-, 2 beta-, 6 beta-, 7 alpha-, 16 alpha-, and 16 beta-hydroxylation and 17-oxidation of testosterone. These results indicate that imipramine has two actions on the liver CYP system (i.e. as an inhibitor of the CYP2D enzyme and as a phenobarbital-type inducer).

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Imipramine	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details
Lidocaine	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details