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PubMedDate not supplied

E- and Z-10-hydroxylation of nortriptyline by human liver microsomes--methods and characterization.

To enable in vitro characterization of nortriptyline 10-hydroxylase activity of microsomal fractions of human liver, methods for the determination of E- and Z-10-hydroxynortriptyline were developed. High performance liquid chromatography (HPLC) with UV-detection or HPLC separation followed by quantitation by gas chromatography-mass spectrometry were used. The microsomal 10-hydroxylation of nortriptyline was linear to 60 min with a protein concentration of 1 mg x ml-1. In 15 human livers a 5-fold variation in activity was found. The formation of the Z-isomer comprised 13 +/- 3% (mean +/- SD) of the total 10-hydroxylase activity. The 10-hydroxylation was inhibited by debrisoquine, sparteine, propranolol, and encainide. No effect or a stimulation of the activity was seen with p-nitroanisole and acetanilide.

Adult↗

PubMed1978

A radioimmunoassay for nortriptyline (and other tricyclic antidepressants) in plasma.

The radioimmunoassay for nortriptyline described here can detect as little 1 microgram/liter of plasma. Within-day precision and day-to-day precision (CV) were +/- 6 and +/- 11%, respectively, over the concentration range 100-200 microgram/liter. The major metabolite hydroxy-nortriptyline, does not cross react with the antiserum. Results so obtained correlate closely with results by a double-isotope derivative dilution technique. The major advantages of this technique over currently available methods are its sensitivity, convenience (many samples can be processed in one day), simplicity, and cost. Further, prior extraction of plasma samples is not required. Cross-reactivity studies have been carried out with all other available tricyclic antidepressants. The antiserum has the ability to bind these drugs, thus radioimmunoassay for all the tricyclic antidepressant drugs can be set up because concurrent use of more than one of these drugs is rare.

Antidepressive Agents, Tricyclic↗

PubMed1978

Measurement of plasma nortriptyline concentrations: radioimmunoassay and gas-chromatography compared.

We compared measurement of plasma nortriptyline by a recently developed radioimmunoassay technique with values obtained by traditional gas chromatography. The coefficient of correlation (r) was 0.98 for 84 samples from 21 controlled patients; for a separate series of 45 samples from 34 patients who were receiving in addition other medication, r was 0.96. Use of radioimmunoassay in the routine determination of plasma nortriptyline concentration is discussed.

Chromatography, Gas↗

PubMed1980

Prediction of steady-state plasma levels of amitriptyline and nortriptyline from a single dose 24 hr. level in depressed patients.

Amitriptyline and nortriptyline plasma levels were measured in depressed outpatients 24 hours after a single dose of amitriptyline and following chronic dosing to steady state. Plasma levels of amitriptyline and nortriptyline measured after the single dose correlated highly with steady state plasma levels. Full use as a test to rapidly place patients on a "therapeutic" dosage of drug will need to await a clear delineation of the relationship between blood levels and clinical response for amitriptyline.

Amitriptyline↗

PubMed1993

High initial nortriptyline doses in the treatment of depression.

BACKGROUND: Guidelines for doses of nortriptyline are generally somewhat vague and usually recommend a fairly wide dose range. Additionally, the safety and utility of beginning treatment at higher initial doses have not been adequately investigated. METHOD: Nortriptyline treatment was initiated with a 75- to 125-mg dose depending on weight in 26 depressed inpatients in an open-label study. RESULTS: The mean Hamilton Rating Scale for Depression score decreased by 45% within 1 week (p < .001) and remained essentially unchanged at the end of Week 2. Orthostatic hypotension was the side effect of major concern since it is virtually the only significant cardiovascular effect in young healthy individuals treated with tricyclic antidepressant medication. Only 2 patients developed orthostasis, which required additional treatment with fludrocortisone, and no patients were dropped from the study due to side effects. None of the patients evidenced significant ECG changes. Twenty-one patients (81%) reached therapeutic drug levels on the initial dose regimen by the end of Week 1. CONCLUSION: Subjects tolerated high initial doses well and appeared to reach significant benefit within the first week. However, double-blind controlled studies are needed before any definitive conclusions can be drawn.

Adult↗

PubMed1995

Double-blind comparison of paroxetine and nortriptyline on the postural stability of late-life depressed patients.

This article describes a 6-week study evaluating body sway during double-blind therapy with nortriptyline versus paroxetine in geriatric patients. Body sway was measured with patients' eyes open, then closed, using a stable force platform at 4 timepoints: before starting antidepressant medication, and after 1, 2, and 6 weeks of treatment. Measures such as the length (L) of path of the center of pressure (COP) and the area included within the COP path were selected for quantitative assessment of stability. A repeated measures analysis of variance (ANOVA) model with planned comparisons was used to examine the pair-wise difference at baseline and Weeks 1, 2, and 6 of treatment. No significant difference was found in body sway parameters over the 6 weeks of study for patients treated with either nortriptyline or paroxetine.

Aged↗

PubMed1977

Specific radioimmunoassay for amitriptyline and nortriptyline in plasma.

A specific radioimmunoassay (RIA) for the determination in plasma of the widely used tricyclic antidepressant amitriptyline (AT) and its major metabolite nortriptyline (NT) has been developed employing 3H-AT as the radioligand and a rabbit antiserum to a bovine serum albumin conjugate of N-succinyl-nortriptyline. Although the antiserum cross-reacts almost equally well with AT and NT, specificity is achieved by selective extraction of each compound from plasma at a different pH. A unique aspect of the assay is that at no time during the entire extraction procedure is the AT or NT taken out of solution. Both compounds are back extracted from the organic phase into 0.1 N HC1 and the acid fraction subjected to RIA directly. The method has a limit of sensitivity of about 2 ng/ml using a 0.5 ml sample of plasma. Satisfactory agreement was obtained for plasma levels of AT and NT when determined by the RIA and a specific GC/MS procedure. The correlation coefficients were 0.89 and 0.98 for AT and NT, respectively. THE RIA has been used to measure steady-state levels of AT and NT in man after chronic administration of AT and following a single oral 75 mg dose. The method also lends itself for the specific determination of NT alone in subjects receiving therapeutic doses of NT.

Amitriptyline↗

PubMed1976

A sensitive method for the determination of amitriptyline and nortriptyline in human plasma.

A highly sensitive and reproducible GLC technique for the quantitation of amitriptyline and nortriptyline is described. The lower limit of detection is less than 1 ng/ml. 5 ng/ml samples (3 ml aliquots) can be accurately quantified (C of V less than 5%). Steady state data are reported together with data on amitriptyline and nortriptyline levels obtained in a volunteer who ingested a single oral dose (25 mg) of amitriptyline (Elavil).

Adult↗

PubMed1976

[Proceedings: Age and sex specificity of organ distribution and metabolism of chlorprothixene and nortriptyline in the rat (author's transl)].

Chlorprothixene and its N-desmethyl derivative are found to be present in the brain, liver, kidneys and lungs of young animals in larger quantities and for a longer period of time than in older animals. The N-demethylation rate is significantly higher in the brain, liver, kidney and lungs of older animals than of young animals. In general, female animals show higher levels in the organs. The "youth dependent" hyper-content exceeds that of the older animals by the factor of appr. 2. For nortriptyline there is an inverse ratio, with more nortriptyline and desmethylnortriptyline in the older animals than in the young ones. The organ content is also higher in the females than in the males. The "age-dependent" hyper-content exceeds that of the younger animals by the factor of appr. 2. These results correspond roughly with the differences in toxicity.

Aging↗

PubMed1978

Double-antibody enzyme immunoassay for nortriptyline.

beta-D-Galactosidase (EC 3.2.1.23) from Escherichia coli was conjugated to desmethylnortriptyline by means of a bifunctional cross-linking reagent, dimethyl adipimidate, and used in a double-antibody immunoassay for nortriptyline. Eighty percent of the enzyme activity was retained after conjugation; 75% of the enzyme was conjugated to desmethylnortriptyline. In the final immunoassay the enzyme activity of the bound fraction was determined with o-nitrophenyl-beta-D-galactopyranoside as substrate. The sensitivity, precision, and simplicity of the enzyme immunoassay compared favorable with that of a published radioimmunoassay method. Results for nortriptyline in plasma samples correlated well with those determined by either radioimmunoassay or gas-chromatography.

Cross Reactions↗

PubMed2000

Age and nortriptyline concentrations in plasma ultrafiltrate.

OBJECTIVES: Since plasma protein binding of tricyclic antidepressants may be relevant to treatment effects and can be influenced by age-associated factors, we examined both plasma ultrafiltrate and total concentrations of nortriptyline (NT) in patients and compared these to age. We hypothesized negative associations with age of both ultrafiltrate NT and the ratio of ultrafiltrate NT to total plasma NT. METHODS: Patients with major depression at a psychiatric service treated with a stable dose of NT were studied. Trough plasma ultrafiltrate NT concentrations and total plasma NT concentrations were measured by high performance liquid chromatography. Concentrations were corrected for dose. RESULTS: Eighty-seven patients aged 26 - 88 years were studied. Ultrafiltrate NT concentrations and the ratio of ultrafiltrate NT to total NT concentrations were both significantly negatively associated with age. Total NT concentrations were not significantly associated with age. CONCLUSIONS: Relatively low ultrafiltrate NT concentrations in older patients may reflect lower tissue exposure at a given total plasma NT concentration. This could be relevant to toxic and therapeutic effects. Studies of relationships between non-bound drug concentrations and NT treatment outcomes across the age span are needed.

Adult↗

PubMed1978

No circadian effect on nortriptyline kinetics in man.

Kinetics of a single 100-mg dose of nortriptyline were studied in 10 normal men who took this dose at 9 A.M. in the morning and on another occasion at 9 P.M. Only minimal differences in kinetic parameters were observed, none enough to be of any clinical consequence. A rather high first-pass metabolism of the drug was evident by high plasma concentrations of 10-hydroxynortriptyline. It is thus unlikely that the recent custom of giving single daily doses of tricyclic antidepressants in the evening excludes regimens with more favorable drug kinetics.

Administration, Oral↗

PubMed1994

Sources of prediction error when using a Bayesian method to evaluate nortriptyline serum concentrations.

A Bayesian method was used to evaluate nortriptyline (NTP) serum concentrations (Cps) and predict future Cps in two populations: five simulated groups (n = 20 each) with known clearance (CL) and volume of distribution (Vd), and an actual inpatient group (n = 20). The effects of weight, CL, Vd, and magnitude of Cps on absolute prediction error (APE) were evaluated. In simulated groups, Cps after two doses of NTP and for steady-state were calculated for normal, increased, and decreased Vd and CL. In the actual patient group, Cps were measured in the first few days after starting NTP administration and again during maintenance therapy. The first Cps were used in the Bayesian program to estimate CL and Vd to predict the second Cps. In the simulated group, PE and APE differed significantly between normal and decreased values of CL. A large Vd resulted in less of a change in PE or APE in these subjects, but when combined with low CL led to the largest errors. In the actual patient group, PE was -5.9 +/- 19.2 ng/mL and APE was 15.4 +/- 12.6 ng/mL. In these patients, only body weight was correlated with the percent APE (r = 0.607, P = 0.005). The Bayesian method performs well clinically, but increased Vd and decreased CL can lead to higher PE. Clinically, the only factor that predicted higher APE was obesity. This may reflect an effect on Vd, and in these patients, a high APE may occur.

Adult↗

PubMed1976

Comparison of observed and predicted first-pass metabolism of nortriptyline in humans.

The extent of first-pass metabolism of nortriptyline, calculated by comparing the areas under the plasma concentration-time curves following intravenous and oral dosing in six individuals, varied from 41 to 54%. Theoretically predicted values ranged from 41 to 61% based on a plasma flow model, indicating that the clearance takes place mainly from the plasma, which does not represent the whole blood concentration.

Humans↗

PubMed1987

Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites.

Treatment of endogenous depression with nortriptyline (NT), at a daily dose of 150 mg, resulted in a pronounced improvement of seven of ten patients investigated. The concentration of the norepinephrine metabolite HMPG in cerebrospinal fluid (CSF) decreased by 29% (P less than 0.01) after 3 weeks of treatment. There was no significant effect of treatment on the serotonin and dopamine metabolites 5-HIAA and HVA. In previous larger materials, however, a decrease of 5-HIAA in CSF has been demonstrated. Platelets from the patients showed an increase in Km for serotonin uptake in response to NT treatment. The IC50 value of NT for serotonin uptake inhibition was 940 nM, while the corresponding value of the major metabolite of NT, i.e. E-10-OH-NT, was much higher (6700 nM). Thus, during treatment, the parent drug and not the metabolite was responsible for the serotonin uptake inhibition in platelets. There was a close correlation between Km and the plasma concentration of NT after 1 week of treatment (r = 0.88, P less than 0.01) but not after 3 weeks of treatment (r = 0.48; ns). There was no uniform effect of NT treatment on Vmax. It is concluded that clinical NT treatment results in uptake inhibition not only in norepinephrine but also in serotonin neurons.

Adult↗

PubMed1976

Self-inhibiting action of nortriptylin's antidepressive effect at high plasma levels: a randomized double-blind study controlled by plasma concentrations in patients with endogenous depression.

Below the toxic plasma level of nortriptyline (NT) an upper therapeutic limit has been postulated in patients with endogenous depression. If so the clinical significance is obvious and a double-blind, randomized study was performed in order to solve this problem. Two groups of patients were controlled at different plasma levels (less than 150 ng/ml and less than 180 ng/ml). The degree of depression was rated weekly. Only about one third (n equals 24) of the patients originally included, were carried through the full protocol, the most prominent reason for drop out beeing spontaneous remission during an initial placebo period. After 4 weeks of NT treatment the majority in the high level group was still depressed, but the difference barely significant (P equals 5.5%). However, a randomized reduction of the plasma level among the patients at the high level resulted in a significant correlation to remission. Evaluation of the total material after 6 weeks of NT treatment demonstrated a strong correlation of high plasma level to poor antidepressive effect of NT. No correlation could be obtained between side-effects, which were few, and plasma level. The non-proteinbound fraction in plasma was found to 7% (SD 1.83) by simultaneous determinations of NT in plasma and CSF in 13 patients. The variation in the proteinbinding was not likely to invalidate the over all results based on total NT determination. A therapeutic plasma range of 50-150 ng/ml is recommended.

Adult↗

PubMed1984

Tranylcypromine vs nortriptyline vs placebo in depressed outpatients: a controlled trial.

This study was designed to compare the therapeutic and adverse effects of tranylcypromine (a monoamine oxidase inhibitor), nortriptyline (a tricyclic antidepressant), and placebo. A total of 122 depressed outpatients randomly assigned to double-blind treatment with one of these agents completed the 4-week protocol. Treatment groups were balanced for proportions of endogenous versus nonendogenous depressions, defined according to the Research Diagnostic Criteria; however, nonendogenous depressions outnumbered endogenous depressions by such a large proportion (4:1) that meaningful statistical comparisons were limited to the nonendogenous group. In this group, both active drugs proved more effective than placebo, with little differences between the two active drugs except in the areas of side effects and of differential sensitivity of the outcome scales to a given drug. It was concluded that tranylcypromine, a drug which has received relatively little use and study in recent years, represents an effective and reasonably safe treatment for nonendogenous depression, although significant advantages over tricyclics with this disorder remain to be demonstrated.

Adolescent↗

PubMed1978

The practical significance of nortriptyline plasma control. A prospective evaluation under routine conditions in endogenous depression.

The problem of the advantage of using nortriptyline (NT) plasma level during treatment for endogenous depression has been approached. In an ordinary psychiatric department, 34 patients had their NT level checked the second week of treatment and their dosage subsequently adjusted, if it was outside the recommended therapeutic plasma range (50--150 ng/ml). A cautious dose policy led to low plasma levels followed by dose increase in about 40% of the patients. Only in a few patients was the plasma level above the upper limit. The general outcome, about 20% failures, was compatible with the best in literature. These and other results suggest that controlling the NT plasma concentration, aiming at a level of around 100 ng/ml, might offer a therapeutic advantage, but only if the department has established a therapeutic strategy that involves such a monitoring system. The therapeutic outcome was the same as or even better in the old-age group than that in patients under 65 years of age.

Aged↗