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 ln (desipramine/imipramine) showed that only ln (mephenytoin S/R) correlated (p = 0.013; r ² = 0.19). For ln (2-hydroxydesipramine/2-hydroxyimipramine) we found that ln (mephenytoin S/R) and ln (4-chlorphenylbiguanide/chloroguanide) correlated (p = 0.001; r ² = 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 fuction tests.