Effect of venlafaxine on imipramine metabolism

This article will review the various agents affecting the central nervous system (CNS) such as the analgesics, antidepressants, anticonvulsants, antipsychotics, and benzodiazepines. Most of the research in pharmacogenetics with the CNS agents have been conducted in the antidepressants. The cytochrome 450 IID6 isozyme system has been shown to influence the disposition of the antidepressants and antipsychotics. Amitriptyline metabolism to nortriptyline and nortriptyline conversion to its 10-OH metabolite were shown to be influenced by the IID6 isozyme. Interestingly, imipramine metabolism to desipramine is only partially related to the IID6 isozyme. Biotransformation of imipramine to its 2-OH metabolite was shown to be affected by the IID6 isozyme, but its metabolism to the 10-OH remains to be investigated. Of the antipsychotic drugs, haloperidol and thioridazine are two agents most studied. Haloperidol is converted to a reduced metabolite via a ketone reductase enzyme. The reduced metabolite is oxidized back to Haloperidol. This oxidation pathway was reported to be affected by the IID6 isozyme. Thioridazine metabolism to mesoridazine and conversion of codeine to morphine appear to be also influenced by CP-450 IID6. Other 450 isozymes are reported to be involved with other CNS agents.

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Studies on 14C-imipramine Metabolism in the Isolated Perfused Rat Liver

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y74-059 ◽

1974 ◽

Vol 52 (3) ◽

pp. 441-450 ◽

Cited By ~ 8

Author(s):

Mervin Moldowan ◽

G. D. Bellward

Keyword(s):

Rat Liver ◽

Substrate Concentration ◽

High Efficiency ◽

Liver Perfusion ◽

Accurate Method ◽

Isolated Perfused Rat Liver ◽

Perfused Rat Liver ◽

Maximal Rate ◽

Perfusion Fluid ◽

Imipramine Metabolism

An analytical procedure for the measurement of 14C-imipramine and its metabolites in liver, bile, and perfusion fluid has been studied using the isolated perfused rat liver technique. The extraction efficiency and specificity have been found to be high (efficiency with liver perfusion, 90–100%; specificities: imipramine, 96.6%; desmethylimipramine, 96.7%; imipramine-N-oxide, 90%). The hydroxylation of imipramine was close to the maximal rate at a substrate concentration of 0.5 × 10−4 M (15 min perfusion). The demethylation reaction reached a maximal rate at an estimated substrate concentration of 1.25 × 10−4 M. The formation of the N-oxide metabolite remained linear at 2 × 10−4 M imipramine. It was found that the half-life of imipramine in the perfusion fluid was not an accurate method of estimating imipramine metabolism as a result of a change in distribution. Exogenous desmethylimipramine inhibited the hydroxylation reaction; inhibition of demethylation required higher concentrations.

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