Active Hydroxymetabolites of Antidepressants

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.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship between clinical effects of fluvoxamine and the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients

“…These results suggest that not only FLV but also FLA contributes to the antidepressant effect during FLV treatment, and the combined Css best correlates with the therapeutic outcome. Similar phenomena have been suggested for nortriptyline and 10-hydroxynortriptyline (Nordin and Bertilsson 1995), desipramine and 2-hydroxydesipramine (Nelson et al 1988), and mianserin and desmethylmianserin (Otani et al 1991).…”

“…Furthermore, although involvement of metabolites in the antidepressant effect has been suggested for some antidepressants, e.g. nortriptyline (Nordin and Bertilsson 1995), desipramine (Nelson et al 1988), and mianserin (Otani et al 1991), none of these studies has considered the metabolites of FLV.…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…For the norepinephrine transporter, nortriptyline free concentrations are about the same as the potency value, while for amitriptyline the free concentrations are about a fifth of the reported affinity suggesting a similar level of occupancy for the norepinephrine transporter with the metabolite contributing the greater share (Breyer-Pfaff et al, 1982). This is all further complicated by the observation that 10-hydroxynortriptyline also can contribute to effect (Nordin and Bertilsson, 1995). After amitriptyline administration, this metabolite has a concentration that is above its IC 50 for the norepinephrine transporter (measured in whole human plasma).…”

Addressing phenoconversion: the Achilles' heel of personalized medicine

“…In 1995, the term 'ultrarapid metabolizers' was formalized to designate a defined subgroup of the population [108]; however, none of these reports introduced the acronym UM. In 1995, Nordin and Bertilsson reverted to using the term 'rapid hydroxylators' (again without an acronym) in their review of the active hydroxy-metabolites of antidepressants [109]. In 1993, Mura et al [110] confirmed that in EM subjects, part of the phenotypic heterogeneity could be explained by a subgroup of individuals heterozygous for a mutant allele.…”