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PubMed1981

E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation.

Eight healthy subjects [who were phenotyped with a debrisoquine (D) hydroxylation test] were selected to cover a wide range in the ratio between D and 4-hydroxydebrisoquine (4-OH-D) in the urine. After a single oral dose of nortriptyline (NT) the metabolic clearance by 10-hydroxylation in the E-position, but not in the Z-position, correlated closely to the metabolic ratio D/4-OH-D (rs = -0.88, p less than 0.01). This indicates that common enzymatic mechanisms are involved in the hydroxylation of D and the E- but not the Z-10-hydroxylation of NT. Slow hydroxylators of NT and D excreted less 10-hydroxynortriptyline in urine and had lower plasma clearance of NT than the rapid hydroxylators. The strong correlation (r = 0.96) between the total plasma clearance of NT and the metabolic clearance by E-10-hydroxylation shows that this metabolic reaction is important in the disposition of the drug.

Debrisoquin↗
PubMed1982

Plasma binding variations of amitriptyline and nortriptyline.

The importance of variation in plasma binding in the uncertain correlation between total plasma concentration and the antidepressive effect of amitriptyline (AT) and its active metabolite nortriptyline (NT) was examined. Plasma binding of AT and NT in 131 plasma samples from 87 patients was analyzed by equilibrium dialysis at 37 degrees for 3 hr. There was a twofold variation in percent unbound AT and NT (range 3.5% to 8.6% and 5.4% to 11.3%) and there was no correlation between percent and unbound drug and total drug concentration (range 54 to 6910 nmol/l and 77 to 3420 nmol/l for AT ant NT). The correlation coefficient relating unbound drug concentration of AT and NT to total concentration in plasma was 0.99 for the whole group and 0.16 for the NT therapy control patients, with total plasma concentrations within the therapeutic range. At therapeutic concentration AT was 66.6% and 63.5% bound to purified isolated orosomucoid (alpha 1-acid glycoprotein) and albumin, at physiologic concentrations. The binding to isolated lipoproteins was not examined, but no correlation was found between percent unbound AT and NT and plasma concentration of triglycerides, cholesterol, or orosomucoid.

Adult↗
PubMed1982

Significance of lipoproteins in serum binding variations of amitriptyline, nortriptyline, and quinidine.

Using isotope technique, the serum binding of amitriptyline (AT), nortriptyline (NT), and quinidine (Q) was measured by equilibrium dialysis in sera containing varying amounts of lipoproteins. Sera were obtained from 10 fasting subjects with normal to grossly elevated levels of cholesterol, triglycerides, or both. When the lipoproteins were removed from eight of the sera by a standard ultracentrifugation technique, the ratio bound/unbound (B/F) AT decreased an average of 47% (range 30% to 68%), NT an average of 54% (range 39% to 67%), and Q an average of 6% (range 0 to 16%). This decrease in the ratio B/F correlated linearly with the sum of serum concentrations of cholesterol and triglycerides for AT (r = 0.88) and NT (r = 0.82), but not for Q (r = 0.15). In three lipoprotein-depleted sera resuspended with lipoproteins at eight different concentrations ranging from 0 to 100% of the original content, there was a linear correlation between the ratio B/F for AT and NT and the lipoproteins, as evidence by cholesterol or triglycerides concentrations (r = 0.97 to 0.99), but not for Q (r = -0.17 to 0.36). Finally, in the original 10 serum samples, there was a linear correlation between the ratio B/F and the serum lipoproteins (sum of cholesterol and triglycerides) for AT (r = 0.89) and NT (r = 0.68), whereas there was no such relationship for Q (r = -0.15). These data indicate that basic drugs differ in binding characteristics (probably depending on lipophility).

Adult↗
PubMed1982

Nortriptyline formation after single oral and intramuscular doses of amitriptyline.

Oral (50 mg) and intramuscular (25 mg) amitriptyline (AT) was given to six normal subjects and the area under the plasma concentration-time curve (AUC) for nortriptyline (NT) formed was calculated. There was no difference between the AUCs (corrected for dose) after the two routes of administration. The ratio between the AUCs (corrected for dose) after the two routes of administration. The ratio between AUCoral and AUCim averaged 0.95 (range 0.69 to 1.13). After intramuscular AT maximum NT plasma concentration was reached after 24 to 48 hr, whereas it was 8 to 24 after oral dosing.

Administration, Oral↗
PubMed1984

Nortriptyline and debrisoquine hydroxylations in Ghanaian and Swedish subjects.

Eleven Ghanaian and 12 Swedish subjects phenotyped with a debrisoquine (D) hydroxylation test were given a single oral dose of nortriptyline (NT). Much the same percentage of the given NT dose was excreted as 10-hydroxy-NT (10-OH-NT) by Ghanaians (43.1%) and Swedes (49.2%). There was a close correlation between plasma clearance of NT by 10-hydroxylation and the D metabolic ratio (D/4-OH-D in urine) in the Ghanaians (rs = -0.95; P less than 0.01) and Swedes (rs = -0.84; P less than 0.01). The E-isomer of 10-OH-NT is the major isomer in both Ghanaians (76% to 92% of total 10-OH-NT) and Swedes (78% to 95%). It is suggested that the E-10-hydroxylation of NT and the 4-hydroxylation of D are similarly coregulated in Ghanaians and Swedes.

Administration, Oral↗
PubMed1987

Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline.

Plasma concentrations of nortriptyline (NT) and its major metabolite 10-hydroxy-NT (10-OH-NT) were measured in 30 patients with depression, treated with NT for 3 weeks. Nine patients who recovered completely had plasma concentrations of NT and 10-OH-NT ranging from 358 to 728 nmol/L and from 428 to 688 nmol/L, respectively. Of the 21 patients who did not recover completely, only four had plasma concentrations within the window limited by these two plasma concentration ranges. A correlation was found between the degree of amelioration and the plasma concentration of NT (rs = 0.469; P less than 0.01). Lumbar punctures were performed in 26 patients before and after 3 weeks of NT treatment. During treatment there was a 30.9% mean decrease in the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). We could not evaluate the extent to which this decrease was caused by NT or 10-OH-NT, respectively, because both are strong inhibitors of noradrenaline uptake. The ratio between the concentration of NT and 10-OH-NT in CSF correlated to the reduction of HMPG in CSF (r = 0.397; P less than 0.05) and to the amelioration of depression (rs = 0.623; P less than 0.001). This might indicate that NT and 10-OH-NT interact on the noradrenaline system in a nonadditive way. During treatment there was a 15.2% decrease in CSF concentration of the serotonin metabolite 5-hydroxyindoleacetic acid. The reduction was significantly correlated to the CSF concentration of NT but not to that of 10-OH-NT. This is in accordance with the fact that NT is a more potent inhibitor of serotonin uptake than is 10-OH-NT. The dopamine metabolite homovanillic acid in CSF decreased significantly by 10.0%. The biochemical data indicate that noradrenergic, serotoninergic, and dopaminergic systems are affected by NT treatment and that 10-OH-NT might be more selective on noradrenergic neurons than the parent drug.

Administration, Oral↗
PubMed1987

Little anticholinergic effect of E-10-hydroxynortriptyline compared with nortriptyline in healthy subjects.

Six healthy male subjects were randomly given nortriptyline (NT) (25 and 50 mg) and placebo in a double-blind, crossover study. An NT dose of 50 mg (but not 25 mg) clearly reduced saliva flow (P less than 0.05) and was therefore used for comparison with the major and active metabolite of NT, E-10-hydroxynortriptyline (E-10-OH-NT). Equimolar doses of both compounds (and placebo) were randomly given to eight healthy male subjects in another double-blind, crossover study aimed to assess the reduction of saliva flow. NT significantly depressed saliva flow compared with both placebo (P less than 0.01) and E-10-OH-NT (P less than 0.05). By contrast, there was no difference between E-10-OH-NT and placebo. This study confirms previous indications that the anticholinergic effect of E-10-OH-NT is considerably less than that of the parent drug NT.

Adult↗
PubMed1976

Therapeutic control of plasma concentrations and long-term effect of nortriptyline in recurrent affective disorders.

Based on the evidence that therapeutic plasma concentration range in fact exists for the tricyclic antidepressant drug, Nortriptyline (range 50-150 ng/ml), three different investigations were under taken in order to clarify some clinical pharmacological problems during long-term treatment with this drug. The possible prophlactic effect of the drug in recurrent affective disorders was specially examined in a group of patients with a high risk of episodes in their unipolar manic-depressive disease. The results highly demonstrate the value of monitoring plasma levels in achieving therapeutic control. Depressive relapses during treatment, for months and years, were only related to therapeutic insufficient plasma levels of the drug.

Adolescent↗
PubMed1982

Quality control of amitriptyline and nortriptyline plasma level assessments: a multicenter study.

Numerous studies report about the relationship between the clinical effectiveness of amitriptyline (At) and the plasma level of this drug and of its most important metabolite, nortriptyline (Nt). These agents are therefore very frequently examined for clinical applications and for research programmes in specialized laboratories. The experience with antiepileptic drugs suggests the necessity of quality controls for antidepressants also. Therefore, five institutions in Western Europe performed two such experiments within a year. Two kinds of blood samples were sent for analysis: 1. plasma samples spiked with different quantities of At and Nt from an untreated subject; 2. plasma samples from patients treated with clinical doses of At. Each laboratory happened to use a different analytical method: TLC, HPLC, GC-NPD, GC-FID and GC-MS. The results clearly show the usefulness and the necessity of quality controls for this category of drugs as well. They form the basis for the improvement of the methods of each laboratory in particular. In this context, intralaboratory quality controls are also possible, if one disposes of two different methods. The findings of this study suggest that published reports on relationships between clinical and pharmacological parameters should be considered critically as to possible methodological bias.

Amitriptyline↗
PubMed2004

The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man.

Amitriptyline (AT), the most widely used tricyclic antidepressant, undergoes oxidative metabolism in the side chain with production of the secondary amine nortriptyline (NT), a primary amine, and the N-oxide amitriptylinoxide (AT-NO); in addition, direct conjugation leads to a quaternary ammonium-linked glucuronide. Hydroxylation of AT or NT at the ethylene bridge of the central seven-membered ring results in four isomeric alcohols and occurs with high stereo- and enantioselectivity, the (-)-(E)-10-hydroxy compounds usually being the major products. The disposition of the alcohols is also partially enantioselective, for instance with regard to glucuronidation and reversible oxidation to ketones. Introduction of a second hydroxy group results in isomeric glycols. Oxidative attack at an aromatic ring is a minor pathway leading to dihydrodiols and phenols. Numerous metabolites originate by combinations of reactions in the ring system and the side chain. AT-NO is by about one-third excreted in unchanged form or as 10-hydroxy derivative; the major part is reduced to AT and metabolized further. The review covers current knowledge on the enzymes participating in the individual pathways. Their quantitative importance is inferred from kinetic studies in volunteers and patients and from experiments in vitro. Clinical consequences of biochemical findings mainly derive from the impact of the polymorphic CYP2D6 mediating (-)-(E)-10-hydroxylation and from its potential inhibition by other psychoactive drugs.

Amitriptyline↗
PubMed2000

A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder.

OBJECTIVES: To study the efficacy and tolerability of nortriptyline (NT) in the treatment of pediatric attention deficit hyperactivity disorder (ADHD). METHODOLOGY: Subjects were outpatient children and adolescents with ADHD ascertained from clinical referrals. Subjects were enrolled in a 6-week open study in which NT was titrated to 2 mg/kg/day as tolerated over 2 weeks. Using either a 30 % reduction in the ADHD rating scale or a score of 1 or 2 on the Clinical Global Impression (CGI) scale for ADHD improvement, responders to treatment were then randomized into a 3-week, controlled discontinuation phase. During this phase, subjects either continued on their current dose of NT or were tapered to placebo under double-blind conditions. Subjects were monitored for symptoms of ADHD, oppositionality, anxiety, and depression. RESULTS: Of the 35 subjects enrolled in the study, 32 completed the open phase and 23 completed the discontinuation phase. The mean dose of NT was 80 mg (1.8 mg/kg/day), resulting in a serum level of 81 ng/ml. At the conclusion of the open 6-week study, NT was related to a significant reduction in ADHD (p < 0.001) and oppositional symptoms (p < 0.001). At the conclusion of the discontinuation phase, the 12 subjects randomized to NT had significantly lower scores on the DSM-IV ADHD symptom checklist than those 11 subjects randomized to placebo (31 versus 21; t = 2.2; p < 0.04). No significant adverse events were observed, and children were noted to have weight gain during the trial. CONCLUSIONS: These data suggest that NT is effective in reducing symptoms not only of ADHD but also of oppositionality. This group of children and adolescents tolerated robust dosing of NT well, with few clinical or cardiovascular adverse events.

Adolescent↗
PubMedDate not supplied

Percutaneous absorption of tricyclic antidepressants: amitriptyline, nortriptyline, imipramine, and desipramine.

The percutaneous absorption of amitriptyline, nortriptyline, imipramine, and desipramine as their hydrochloride salts in vivo was demonstrated without use of a vehicle using the hairless (hr-1/hr-1) mouse as an experimental model for human skin. After topical application of 2 mg of each compound in distilled water, followed by rapid evaporation of the water, concentrations were measured in heart, lung, brain, liver, and blood in 1-, 2-, 4-, and 6-hour study groups. Lung consistently demonstrated the highest concentrations for all four compounds while heart and liver had the lowest. Concentrations in heart remained essentially constant for all compounds during the 6-hour study period. The concentrations in solid tissues were much lower than those commonly seen in man after overdose, whereas the concentrations in blood resembled low therapeutic to toxic concentrations in humans. Percutaneous absorption may provide a feasible route of administration for the tricyclic antidepressants which may lead to improved compliance with fewer gastrointestinal side effects.

Amitriptyline↗
PubMed1992

Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder.

A random assignment, double-blind, placebo-controlled study of nortriptyline in 50 prepubertal 6- to 12-year-olds with Research Diagnostic Criteria and DSM-III major depressive disorder was performed. The protocol included a 2-week placebo wash-out phase and an 8-week double-blind, placebo-controlled phase with weekly plasma level monitoring. Active subjects had their plasma level pharmacokinetically placed at 80 +/- 20 ng/ml by using previously developed tables to determine the starting dose from a plasma level 24 hours after a single dose administered at baseline. The mean plasma level was 89.9 ng/ml. The study population was severely depressed, had a chronic, unremitting course of long duration before the study, had a high percentage of family histories with affective disorder, alcoholism and suicidality, and had a high rate of comorbidity. None of the subjects had ever received tricyclic antidepressants before this study. There was a poor rate of response in both treatment groups (30.8% active, 16.7% placebo). Active subjects did not evidence the anticholinergic side effects reported in adult samples. The implications of these findings for future pharmacotherapy studies of depressed children are discussed.

Child↗
PubMed1992

Baseline and 2- to 3-year follow-up characteristics of placebo-washout responders from the nortriptyline study of depressed 6- to 12-year-olds.

Data are presented on the baseline characteristics and 2- to 3-year follow-up assessments of placebo-washout responders (PWRs) from a previously reported pharmacokinetically designed double-blind placebo-controlled trial of nortriptyline for major depressive disorder in 6- to 12-year-olds. Eleven of the 12 PWRs consented to participate in the follow-up study. At baseline, the only significant difference between the PWRs and the non-PWR subjects was that more females were PWRs. Notably, there were no significant differences with respect to severity, chronicity, age of onset, or comorbid psychopathology. The follow-up assessments showed that the rate of relapse to major depressive disorder and the rate of development of bipolarity were not significantly different for PWRs compared with non-PWRs. The authors discuss these findings vis-à-vis the adult literature and provide recommendations for the use of placebo-washout phases in future double-blind, placebo-controlled psychopharmacology trials in children.

Bipolar Disorder↗
PubMed1993

A retrospective study of serum levels and electrocardiographic effects of nortriptyline in children and adolescents.

OBJECTIVE: We retrospectively evaluated a large pediatric population treated with nortriptyline (NT) in an outpatient psychopharmacology clinic to assess pharmacokinetic and electrocardiographic (EKG) effects. METHODS: A systematic search revealed 82 children and adolescents treated naturalistically with NT. All patients with available EKGs and serum NT levels were included in the series with the exception of those receiving concomitant antipsychotic agents. Forty-three percent of subjects were receiving medications in addition to NT. RESULTS: Patients received an average (+/- SE) NT dose of 2.0 +/- 0.1 mg/kg yielding mean serum NT levels of 105.5 +/- 7.4 ng/mL. There was a linear relationship of NT dose (mg/kg) to serum NT levels (r = 0.50, p < 0.0001). NT treatment resulted in small increases in heart rate, and PR, QRS, and QTc intervals (all ps < 0.01), of similar magnitude in children and adolescents. Individuals with the highest baseline EKG indices had the least amount of change in those indices with NT treatment. There were only a few statistically significant associations between NT dose or serum NT levels and EKG parameters. NT treatment was significantly associated with the onset of asymptomatic sinus tachycardia (heart rate > 100 beats per minute), and prolongation of the EKG QRS (> 100 msec) and QTc (> 440 msec) intervals. CONCLUSIONS: These findings suggest: (1) NT has a predictable dose to level relationship, (2) the effect of NT on the EKG in this age group is mild and similar to that reported with other tricyclic antidepressants, and (3) there are few age-specific differences in NT-induced EKG changes.

Adolescent↗
PubMed1993

Nortriptyline in the treatment of ADHD: a chart review of 58 cases.

OBJECTIVE: The potential benefit of the tricyclic antidepressant medication, nortriptyline (NT), in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD) was evaluated. METHOD: A systematic search was conducted from a computerized data base of all clinic patients in an outpatient pediatric psychopharmacology unit treated with NT for ADHD. The records of the 58 subjects identified (37 children and 21 adolescents) were reviewed for overall response, dose, serum levels, and adverse effects. RESULTS: Ninety-seven percent of the identified subjects had failed to respond to an average of four previous medication trials, 84% had at least one comorbid diagnosis with ADHD, and 47% were receiving at least one concurrent medication. NT doses ranged from 0.4 to 4.5 mg/kg (X +/- SD = 2.0 +/- 1.0 mg/kg) and subjects received NT from 0.4 to 57.9 months (11.9 +/- 14.0 months). Overall, 76% of subjects were considered to have a moderate to marked improvement by an independent rater, which was corroborated by their clinicians. There was no association between response and age, rate of comorbidity, number of previous medication trials, or concurrent pharmacotherapy (all p NS). Although there were no overall differences in serum NT levels between responders and nonresponders, significantly more patients within the suggested therapeutic range in adults of 50 to 150 ng/ml were classified as "markedly improved" than those outside this range (68% versus 35%, p < 0.03). Mild adverse effects were reported in 20 subjects (34%). CONCLUSIONS: These findings suggest that NT may be an effective well-tolerated agent for ADHD children and adolescents. Additional controlled investigations utilizing NT for ADHD should be undertaken.

Adolescent↗
PubMed1995

Nortriptyline-induced fulminant hepatic failure.

We describe, to our knowledge, the first reported case of nortriptyline-induced fulminant hepatic failure. This tricyclic antidepressant drug was taken by a postmenopausal woman for 64 days before her presentation. The absence of fever, rash, or marked eosinophilia, the predominant zone 3 necrosis with bridging, and the latent period favor a metabolic idiosyncratic reaction. The fatal outcome underscores the importance of recognizing the association and discontinuing the offending agent.

Aged↗