Active Hydroxymetabolites of Antidepressants

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Abstract
Hydroxymetabolites of the antidepressants nortriptyline and desipramine, like the parent drugs, inhibit neuronal uptake of noradrenaline (norepinephrine). In both plasma and cerebrospinal fluid (CSF), the concentrations of the 10-hydroxymetabolites of nortriptyline (10-OH-NT) are usually higher than those of the parent drugs, but there is a pronounced interindividual variation in the plasma concentrations. This shows that during treatment with nortriptyline, hydroxymetabolites exert, at least in some patients, major effects on brain noradrenaline neurons. Hydroxymetabolites of antidepressants are formed by the polymorphic cytochrome P450 enzyme CYP2D6. Nortriptyline is hydroxylated by this enzyme in a highly stereospecific way to the (−)-enantiomer of E-10-OH-NT. Among Caucasians, 7% are poor metabolisers of the CYP2D6 probe drug debrisoquine. These patients will form very little hydroxymetabolite. The affinity of E-10-OH-NT for muscarinic acetylcholine receptors in vitro was only one-eighteenth of the affinity of nortriptyline for these receptors. In healthy individuals, nortriptyline decreased saliva flow to a significantly greater extent than either E-10-OH-NT or placebo. In an ultrarapid hydroxylator of nortriptyline treated with very high doses of nortriptyline, the plasma concentration of unconjugated 10-OH-NT was very high without any sign of anticholinergic adverse effects. These results show that hydroxymetabolites of nortriptyline have much less anticholinergic effect than the parent drug. When racemic E-10-OH-NT per se was given to healthy individuals, the plasma concentration of the (−)-enantiomer was 5-fold higher than that of (+)-E-10-OH-NT. The 2 enantiomers were eliminated in parallel with an elimination half-life of 8 to 10 hours. A combined in vitro and in vivo investigation showed that a mean of 64% of (+)-E-10-OH-NT was glucuronidated in the liver and subsequently eliminated in urine. Of the administered (−)-enantiomer, a mean of 36% was eliminated as glucuronide formed in the intestine and 35% was actively secreted as unchanged form in urine. Plasma protein binding, determined by ultrafiltration, of the (+)- and (−)-enantiomers of E-10-OH-NT was 54 and 69%, respectively, which is less than that of nortriptyline (92%). The concentration of E-10-OH-NT in CSF was 50% of the concentration of unbound in plasma. There seems to be a stereoselective active transport of E-10-OH-NT from the CSF to blood. We administered racemic E-10-OH-NT to 5 patients during a major depressive episode. During the study period of 3 weeks, the oral daily dose was increased from 75 to 225mg. The mean depression score decreased by more than 50%, but as the study was noncomparative and nonblinded this needs to be confirmed. Only minor adverse effects were recorded. The concentration of the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG) in CSF decreased significantly (by a mean of 18%). Therefore, at the doses given, there was inhibition of noradrenaline uptake in central noradrenaline neurons. Hydroxymetabolites might contribute to biochemical and clinical effects during treatment with antidepressants. Compared with the parent drug, the most investigated metabolite E-10-OH-NT has: (i) similar uptake inhibition in noradrenaline neurons; (ii) considerably less anticholinergic adverse effects; (iii) less cardiotoxicity; (iv) less interindividual variation in pharmacokinetics and metabolism; and (v) similar antidepressant effects, although this needs to be confirmed. These results imply that E-10-OH-NT might be a better antidepressant than nortriptyline. Therefore, additional clinical investigations of E-10-OH-NT should be undertaken.