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


CONCLUSIONS
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.
Madsen
H
H
Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, Denmark.
Rasmussen
B B
BB
Brøsen
K
K
D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D006801:Humans; D007099:Imipramine / Q000493:pharmacokinetics*; D008297:Male; D008745:Methylation; D006899:Mixed Function Oxygenases / Q000502:physiology*; D010641:Phenotype; D012044:Regression Analysis
D000929:Antidepressive Agents, Tricyclic; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007099:Imipramine