Imipramine demethylation in vivo: impact of CYP1A2, CYP2C19, and CYP3A4.

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Madsen H, Rasmussen BB, Brosen K

Imipramine demethylation in vivo: impact of CYP1A2, CYP2C19, and CYP3A4.

Clin Pharmacol Ther. 1997 Mar;61(3):319-24.

PubMed ID

9084457 [ View in PubMed

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Abstract

OBJECTIVE: To further substantiate the role of CYP1A2 and CYP3A4 for the N-demethylation in vivo. At least three different P450s appear to be responsible for the N-demethylation of imipramine to desipramine in vivo: CYP1A2, CYP2C19, and CYP3A4. The role of CYP2C19 in this regard is well documented, but for the two other P450s the evidence is either indirect or based on in vitro studies. METHODS: Phenotypic tests for imipramine N-demethylation, CYP1A2 (caffeine testing), CYP2C19 (mephenytoin and chloroguanide [proguanil] testing), and CYP3A4 (hydrocortisone and quinidine testing) were carried out in 32 healthy young Danes; all were poor (n = 31) or extremely slow extensive metabolizers (n = 1) of sparteine. RESULTS: By exclusion of the insignificant log-transformed variables, multiple regression analysis for In (desipramine/imipramine) showed that only in (mephenytoin S/R) correlated (p = 0.013; r2 = 0.19). For in (2-hydroxydesipramine/2-hydroxyimipramine) we found that in (mephenytoin S/R) and in (4-chlorophenylbiguanide/chloroguanide) correlated (p = 0.001; r2 = 0.41). CONCLUSION: We did not find in vivo evidence of either CYP1A2 or CYP3A4 activity in the N-demethylation of imipramine. This could be due in part to inadequate CYP1A2 and CYP3A4 in vivo function tests.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Imipramine	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details