Nortriptyline metabolite

In one study, 15 healthy subjects were given a single 50-mg dose of amitriptyline 2 hours after taking the ninth dose of semisodium valproate 500 mg every 12 hours. The maximum plasma levels and AUC of amitriptyline were raised by 19% and 30%, respectively. The corresponding values for the nortriptyline metabolite were 28% and 55%, respectively. A study in 6 patients with depression found that amitriptyline 100 mg daily for 3 weeks produced a 43% increase in the volume of distribution and a 16% increase in the plasma half-life of a single 400-mg intravenous dose of sodium valproate. The AUC and total body clearance of valproate were not significantly changed. ... 

Fi re 4.15 Separation of the tricyclic antidepressant amitriptyline and its major metabolites on a 10 cm x 4.6 mm I. D. column packed with Spherisorb S5H silica with methanol-aqueous ammonium acetate (9 1), pH 9.1, as mobile phase at a flow rate of about 1 ml/min. Peak identification 1 > amitriptyline-N-oxide 2 amitriptyline 3 - E-lO-hydroxyamitriptyline 4 - Z-10-hyroxyamitriptyline 5 desmethylnortrlptyline 6 nortriptyline 7 E-lO-hydroxynortriptyline and 8 - Z-lO-hydroxynortriptyline. (Reproduced with permission from ref. 271. Copyright Elsevier Scientific Publishing Co.)... 

Yue, Q.Y. et al. (1998). Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin. Pharmacol. Ther., 64, 384-90. 

Interaction with drug metabolism liquorices, which are the most commonly used herbs in TCM can increase metabolites (e.g., nortriptyline, desipramine, and norclomipramine) of tricyclic antidepressants (TCAs) and may produce more side effects (such as dry mouth, constipation, palpitation, etc.) (Xu, 2004 Zhu Huang, 2004). 

Solid phase extraction (SPE) has been used to efficiently extract several types of antidepressants, which can then be conveniently analyzed on GC-NPD. One assay extracted and analyzed viloxazine, venlafaxine, imipramine, desipramine, sertraline, and amoxapine from whole blood in one procedure (Martinez et al., 2002). The same laboratory analyzed fluoxetine, amitriptyline, nortriptyline, trimipramine, maprotiUne, clomipramine, and trazodone in whole blood in one assay (Martinez et al., 2003). SPE has also been used for the simultaneous analysis of TCAs and their metabolites by de la Torre et al. (1998). 

The metabolism and elimination of TCAs takes several days to occur, the elimination half-life ranging from 20 hours for amitriptyline to 80 hours for protriptyline. The half-life values for the desmethylated metabolites such as desmethylimipramine and nortriptyline are approximately twice those of the parent compounds imipramine and amitriptyline. It is also well established that the half-life values of the TCAs are considerably greater in the elderly, which predisposes such patients to a greater possibility of severe side effects. 

These two drugs can conveniently be considered together, as nortriptyline is an active metabolite of amitriptyline. The possibility that nortriptyline is the major, or even sole, agent through which amitriptyline exerts its therapeutic effect is unlikely since the two drugs have different effects upon adrenergic nerves. 

Maprotiline (Ludiomil) and amoxapine (Asendin) are heterocyclic antidepressant agents that are not members of the tricyclic family. However, their pharmacology is so similar to that of the tricyclic amines that they are included for discussion purposes with this class of agents. Desipramine and nortriptyline are major metabolites of imipramine and amitriptyline, respectively. 

Clinically meaningful plasma levels are available for imipramine, desipramine, and nortriptyline. For imipramine, the sum of the plasma levels of imipramine and the desmethyl metabolite (desipramine) should be greater than 200-250 ng/mL. Desipramine levels should be greater than 125 ng/mL. A therapeutic window has been noted for nortriptyline, with optimal response between 50 and 150 ng/mL. These therapeutic levels are based on steady-state concentrations, which are reached after 5-7 days of administration of these medications. Blood should be drawn approximately 10-14 hours after the last dose of medication. 

The ratio of parent drug to desmethylated metabolite at steady-state has been reported to range from 0.47 to 0.70 for imipramine desipramine and from 0.83 to 1.16 for amitriptyline nortriptyline. These typical ratios can be used to help distinguish between an acute overdose (increased ratios) versus a steady-state situation (normal ratios). 

The secondary amine TCAs, including desipramine and nortriptyline, lack active metabolites and have fairly linear kinetics. These TCAs have a wide therapeutic window, and serum levels are reliable in predicting response and toxicity. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

Using the same protocol as in the study of Dalen et al. in Caucasians (48), we investigated the influence of the Asian specific CYP2D6 10 allele on the disposition of nortriptyline in Chinese subjects living in Sweden (50). Morita et al. (51) related the CYP2D6 10 allele to steady-state plasma levels of nortriptyline and its metabolites in Japanese depressed patients. From these two studies it may be concluded that the Asian CYP2D6 10 allele... 

Dahl M-L, Bertilsson L, Nordin C. Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite relationship to the CYP2D6 genotype. Psychopharmacology 1996 123 315-319. 

Morita S, Shimoda K, Someya T, Yoshimura Y, Kamijima K, Kato N. Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese patients impact of CYP2D6 genotype on the hydroxylation of nortriptyline. J Clin Psychopharmacol 2000 20 141-149. 

Imipramine, desipramine, amitriptyline, nortriptyline, trimipramine, clomipramine, lofepramine, amoxapine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipram, sulpiride, tandspirone, methylpheni-date, melitracen Amitriptyline, imipramine, trimipramine, clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, reboxetine, viloxazine, doxepin, maprotiline, mianserine, mirtazapine, moclobemide, trazodone, opipramol (and some metabolites)... 

Nortriptyline Secondary amine First metabolite of amitriptyline... 

Nortriptyline intoxication secondary to terbinafine has been observed in a woman with a major depressive disorder (214). After rechallenge her serum nortriptyline concentration rose and the serum concentrations of its two hydroxylated metabolites fell. She had a normal genotype for CYP2D6, suggesting that this interaction can occur even in people without reduced CYP2D6 activity. 

One immediately below and one irrmediatdy above the parent dug both strorgly fluoresce Nortriptyline a second metabolite sometimes occurs betweai amitrptyline and nortriptylhe... 

Large genetic differences in rate of metabolism concentrations of drug and metabolite (nortriptyline) cannot be predicted from dosage. Evidence for correlation between plasma concentrations and therapeutic response is mainly negative. 

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