IMIPRAMINE DEMETHYLATION IN-VIVO - IMPACT OF CYP1A2, CYP2C19, AND CYP3A4

Objectives: 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 eithe r indirect or based on in vitro studies.Methods: Phenotypic tests for imipramine N-demethylation, CYP1A2 (caffeine testing), CYP2C19 (mephen ytoin and chloroguanide [proguanil] testing), and CYP3A4 (hydrocortiso ne 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-transfo rmed variables, multiple regression analysis for in (desipramine/imipr amine) showed that only ln (mephenytoin S/R) correlated (p = 0.013; r( 2) = 0.19), For In (2-hydroxydesipramine/2-hydroxyimipramine) we found that ln (mephenytoin S/R) and ln (4-chlorphenylbiguanide/chloroguanid e) 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-demethylat ion of imipramine. This could be due in part to inadequate CYP1A2 and CYP3A4 in vivo function tests.