Imipramine: a model substance in pharmacokinetic research

The pharmacokinetics of imipramine have been studied over a period of 20 years. Imipramine is rapidly and almost completely metabolized with the formation of desipramine (desmethylation), 2-hydroxy metabolites and subsequent glucoronide coupling. Imipramine has a high clearance (0.8-1.5 l/min) and a corresponding high first pass elimination (30-70%). Volume of distribution is high (650-1100 1) and half-lives accordingly of medium length (6-12 h). The 2-hydroxylation which is the most important step of elimination is mediated via microsomal cytochrome P450 isozyme that exhibit monogenetic polymorphism such that 5-10% of the population have a severely reduced clearance. Co-administration of neuroleptics may also considerably impair the 2-hydroxylation. Steady-state levels of imipramine and desipramine varies considerably among individuals mainly due to variations in metabolism, but also to a smaller extent due to variations in binding to plasma proteins. The variations in steady-state concentrations appear to have clear implication for the clinical effects of imipramine.