Stereospecific 10-hydroxylation of nortriptyline — genetic aspects and importance for biochemical and clinical effects

Abstract

The plasma level of the tricyclic antidepressant nortriptyline is an important determinant for its clinical effects (cf. Sjöqvist et al., 1980). The therapeutic effect is related to the plasma level in a curvilinear manner, with poor outcome both at low and very high plasma concentrations (Asberg et al., 1971). There are two main reasons why nortriptyline has become one of the most thoroughly investigated antidepressants: (a) analytical methods were developed very early for measurement of low plasma levels of this secondary amine, and (b) it was initially thought that nortriptyline had no active metabolites (in contrast to the tertiary amines amitriptyline and imipramine). It was later shown that the major metabolite of nortriptyline, i.e. 10-hydroxy-nortriptyline, is almost as potent as the parent drug in inhibiting the uptake of norepinephrine (NE) in rat brain slices (Bertilsson et al., 1979). The E- and Z-10-OH-nortriptyline isomers (figure 1) were equipotent in this respect. It was also shown that the plasma levels of 10-OH-nortriptyline often exceeded those of the parent drug during nortriptyline treatment. Levels of 10-OH-nortriptyline and nortriptyline in CSF were comparable, showing that the hydroxy metabolites pass into the central nervous system (loc. cit).