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

Otani, Koichi; Nordin, Conny; Åberg‐Wistedt, Anna

doi:10.1111/j.1600-0773.1991.tb02044.x

Cited by 12 publications

(4 citation statements)

References 19 publications

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“…[66] In 4 patients treated with racemic E-IO-0H-NT 225mg daily for 3 weeks, the enantiomers were determined by chiral HPLC.f 66 ] The unbound fractions of (+)-and (-)-E-10-0H-NT were 44 ± 1 and 29 ± 1 %, respectively, which is very similar to the 46 and 31 % previously reported [20] (table III). [3J This is much lower than the unbound fraction of 1O-0H-NT determined by protein binding methods.l 20 ,63,64] In a later study in 5 patients treated with amitriptyline or nortriptyline, we confirmed a low (0.09 to 0.17) CSF to plasma ratio for the concentration of 1O-0H-NT.…”

Section: Distribution and Plasma Protein Bindingsupporting

confidence: 62%

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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Section: Distribution and Plasma Protein Bindingsupporting

confidence: 62%

Active Hydroxymetabolites of Antidepressants

Nordin

Bertilsson

1995

Clinical Pharmacokinetics

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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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“…With the enantiomers of (E)-10-hydroxynortriptyline, evidence has strongly implicated a stereoselective, active transport of the molecule out of the cerebrospinal fluid [6]. In contrast, the difference between the brain levels of the enantiomers of fluoxetine may be the consequences of specific and stereoselective cerebral enzymatic activities [14].…”

Section: Introductionmentioning

confidence: 99%

Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium

1999

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Blood-brain barrier transport of the selective serotonin reuptake inhibitor and antidepressant, citalopram, was studied using monolayers of bovine brain microvessel endothelial cells (BMECs). This study provides for the first time, evidence of a transport mechanism for a selective serotonin reuptake inhibitor (SSRI). Carrier-mediated transport, efflux mechanisms, as well as inhibition of metabolizing enzymes of citalopram were investigated. Citalopram transport was saturable and temperaturedependent suggesting that passage of the drug across BMECs was mediated by a carrier mechanism. Since the apical to basolateral and basolateral to apical permeability coefficients were similar and cyclosporin A, a P-glycoprotein inhibitor, does not modify the transport of citalopram, it appeared that no active efflux systems were involved in this transport. Citalopram is only available as a racemic drug and its pharmacological effect resides mainly in the S-(+)-enantiomer. However, the passage of citalopram enantiomers across BMEC monolayers was not stereoselective. Finally, inhibition of the metabolizing enzymes of citalopram and monoamine oxidases did not modify the permeation of citalopram across BMECs. Collectively, our results suggested that citalopram crosses the blood-brain barrier via a non-stereoselective, bidirectional and symmetrical carrier-mediated mechanism without influences of active efflux mechanisms or monoamine oxidases.

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

Cited by 12 publications

References 19 publications

Active Hydroxymetabolites of Antidepressants

Active Hydroxymetabolites of Antidepressants

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium

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