CSF and plasma levels of nortriptyline and its 10‐hydroxy metabolite.

Nordin, Conny; Siwers, Bo

doi:10.1111/j.1365-2125.1985.tb05086.x

Cited by 21 publications

(9 citation statements)

References 11 publications

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“…After 3 weeks of treatment with NT the mean CSF/ plasma ratio of -10-OH-NT (sum of the enantiomers of both (E)-and (Z)-10-OH-NT) in 25 patients was 0.12 (Nordin et al 1985). This is lower than the plasma unbound fraction of 0.35 reported by both Breyer-Pfaff et al (1982) and Baumann et al (1 986) using equilibrium dialysis.…”

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confidence: 68%

“…The geometrical (Z)-isomer is also formed, but to a minor extent. (E)-10-OH-NT is present in plasma and cerebrospinal fluid (CSF) with a mean concentration higher than that of the parent drug NT (Nordin et al 1985). Compared with NT, (E)-10-OH-NT has about half the potency to inhibit noradrenaline uptake (Bertilsson et al 1979), but much less affinity to muscarinic receptors in vitro (Wagner et al 1984) and also less anticholinergic effects in vivo (Nordin et al 1987).…”

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confidence: 99%

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Stereoselective Efflux of (E)‐10‐Hydroxynortriptyline Enantiomers from the Cerebrospinal Fluid of Depressed Patients

Otani

Nordin

Åberg‐Wistedt

1991

Pharmacology & Toxicology

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In 5 patients treated with nortriptyline or amitriptyline for at least 9 months, the cerebrospinal fluid (CSF)/plasma ratio for 10-hydroxynortriptyline (10-OH-NT) ranged from 0.085 to 0.172, which is similar to the ratio previously measured in patients treated for 3 weeks. In 4 other patients treated with racemic (E)-10-OH-NT, the mean concentration ratio between (-)- and (+)-(E)-10-OH-NT was 3.56 in plasma, 2.39 in plasma ultrafiltrate and 1.42 in CSF (one-way ANOVA; P less than 0.001). The mean free fraction in plasma determined by ultrafiltration for (-)-(E)-10-OH-NT was 28.9 +/- S.D.1.1% and for the (+)-enantiomer 43.7 +/- 0.8% (P less than 0.001) confirming the difference in protein binding shown previously in healthy subjects. There was a correlation between the concentration of 10-OH-NT (sum of enantiomers) in CSF and plasma ultrafiltrate (r = 0.96; n = 7; P less than 0.001). The concentration in CSF was, however, only about 50% of that in the plasma ultrafiltrate and this seems to be due to a stereoselective transport of (E)-10-OH-NT out from the CSF. The secretion from the CSF is more pronounced for the (-)-compared to the (+)-enantiomer, which is consistent with the stereoselectivity of the renal secretion of these compounds.

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confidence: 68%

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confidence: 99%

Stereoselective Efflux of (E)‐10‐Hydroxynortriptyline Enantiomers from the Cerebrospinal Fluid of Depressed Patients

Otani

Nordin

Åberg‐Wistedt

1991

Pharmacology & Toxicology

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“…After 3 weeks of administration of nortriptyline 50 to 150mg daily to 25 depressed patients, it was confirmed that lO-OH-NT concentrations were higher than those of the parent drug in plasma [3] ( fig. 2).…”

Section: Plasma and Cerebrospinal Fluid Concentrations During Maintenmentioning

confidence: 82%

Active Hydroxymetabolites of Antidepressants

Nordin

Bertilsson

1995

Clinical Pharmacokinetics

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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)

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“…10-Hydroxynortriptyline is generated by CYP2D6 and research on the polymorphism in this enzyme has shown that there are differences among CYP2D6 extensive and poor metabolizers, with lower concentrations of the metabolite in the latter. Examination of CSF concentrations have shown that there may be a partial barrier to brain penetration of 10-hydroxynortriptyline, since concentrations are lower than corresponding plasma ultrafiltrate concentrations (Nordin et al, 1985;Bertilsson et al, 1991). Finally, it has been suggested that 10-hydroxynortriptyline could itself be an antidepressant that would have a better side-effect profile because it has less activity at muscarinic receptors.…”

Section: Drugs With Metabolites Possessing Activity At Related Tarmentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacological Reviews

138

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CSF and plasma levels of nortriptyline and its 10‐hydroxy metabolite.

Cited by 21 publications

References 11 publications

Stereoselective Efflux of (E)‐10‐Hydroxynortriptyline Enantiomers from the Cerebrospinal Fluid of Depressed Patients

Stereoselective Efflux of (E)‐10‐Hydroxynortriptyline Enantiomers from the Cerebrospinal Fluid of Depressed Patients

Active Hydroxymetabolites of Antidepressants

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

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