Stereoselective High-Affinity Reduction of Ketonic Nortriptyline Metabolites and of Ketotifen by Aldo-Keto Reductases from Human Liver

Oxidative biotransformation of drugs and other xenobiotics by hydroxylation at an aliphatic carbon atom may produce secondary alcohols that can undergo reversible oxidation by an aldo-keto reductase. An example are the major oxidative metabolites of the antidepressant nortriptyline. These consist of two pairs of enantiomeric alcohols, (−)- and (+)-E- and -Z-10-hydroxynortriptyline, which on administration to human volunteers were only partially excreted in urine in unchanged form or as their glucuronides (Nusser et al., 1988; Dahl-Puustinen et al., 1989). On incubation with human liver fractions, the (+)-enantiomer of E-10-hydroxynortriptyline was preferentially oxidized in the presence of NAD+ to the corresponding ketone E-10-oxonortriptyline (E-10-0xo-NT) which occurs as a minor metabolite in urine of patients (Prox and Breyer-Pfaff, 1987).