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PubMed1997

Cytochromes P450 mediating the N-demethylation of amitriptyline.

AIMS: Using human liver microsomes and heterologously expressed human enzymes, we have investigated the involvement of CYPs 1A2, 2C9, 2C19, 2D6 and 3A4 in the N-demethylation of amitriptyline (AMI), with a view to defining likely influences on its clinical pharmacokinetics. METHODS: The kinetics of formation of nortriptyline (NT) from AMI were measured over the substrate concentration range 1-500 microM, using liver microsomes from four extensive metabolisers (EM) and one poor metaboliser (PM) with respect to CYP2D6 activity. RESULTS: The data were best described by a two-site model comprising a Michaelis-Menten function for a high affinity site and a Hill function for a low affinity site. The activity at the low affinity site was eliminated by triacetyloleandomycin and ketoconazole, selective inhibitors of CYP3A4, such that the kinetics were then described by a two-site model comprising two Michaelis-Menten functions. A further decrease in activity was associated with the addition of the CYP2C9 inhibitor sulphaphenazole such that the residual kinetics were best described by a single Michaelis-Menten function. The addition of quinidine, a selective inhibitor of CYP2D6, along with triacetyloleandomycin and sulphaphenazole produced an additional decrease in the rate of NT formation in all but the PM liver, but did not completely eliminate the reaction. The remaining activity was best described by a single Michaelis-Menten function. Inhibitors of CYP1A2 (furafylline) and CYP2C19 (mephenytoin) did not impair NT formation. Microsomes from yeast cells expressing CYP2D6 and from human lymphoblastoid cells expressing CYP3A4 or CYP2C9-Arg N-demethylated AMI, but those from cells expressing CYPs 1A2 and 2C19 did not. CONCLUSIONS: We conclude that CYPs 3A4, 2C9 and 2D6 together with an unidentified enzyme, but not CYPs 1A2 and 2C19, mediate the N-demethylation of AMI. Thus, the clinical pharmacokinetics of AMI would be expected to depend upon the net activities of all of these enzymes. However, the quantitative importance of each isoform is difficult to predict without knowledge of the exposure of the enzymes in vivo to AMI.

Amitriptyline↗
PubMed1977

Does long term treatment with amitriptyline alter the monoamine oxidase of rat brain?

Amitriptyline, at a concentration of 10(-5) M, inhibits the oxidative deamination of phenylethylamine, tyramine and tryptamine (by 40, 16, and 8 percent, respectively) by rat brain MAO. After the long term administration of amitryptyline, even at a dosage of 20 mg per kg body weight twice daily, there was no detectable influence on the biochemical properties of MAO. These findings indicate that the full antidepressive effect, which only appears after the first 3 weeks of long term treatment, cannot be caused by the inhibition of MAO.

Amitriptyline↗
PubMed1979

Central antiserotonin action of amitriptyline.

Amitriptyline (AMI) was studied in rats snd mice in order to find out whether it had a central antiserotonin activity, previously demonstrated for doxepin - a compound chemically related to AMI. It was observed that AMI at low doses antagonized the head twitch response to L-5-hydroxytryptophan or 5-methoxytryptamine, as well as tryptamine-induced convulsions. In the hind limb flexor reflex preparation of the spinal rat AMI acted as a serotonin antagonist: when administered alone, it did not change the flexor reflex but prevented its stimulation induced by serotoninmimetics (LSD, quipazine, fenfluramine) not affecting that one evoked by noradrenalinemimetics (clinidine). At higher doses, AMI revealed a noradrenolytic activity. The results indicate that AMI, similarly as doxepin, has a central antiserotonin activity.

5-Hydroxytryptophan↗
PubMed2001

Serum levels of amitriptyline and therapeutic effect in non-delusional moderately to severely depressed in-patients: a therapeutic window relationship.

In a prospective, open clinical study, the relationship between serum levels of amitriptyline (At) and nortriptyline (Nt) and the therapeutic effect after 6 weeks of treatment was investigated. Serum levels were measured by gas-liquid chromatography and the therapeutic effect was assessed by the Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression Scale (CGI). A number of 25 non-delusional, moderate to severely depressed inpatients were included. A therapeutic window relationship was detected by means of regression analysis (quadratic model). Low and high serum levels were associated with low therapeutic effect. In an intermediate range, the probability of good therapeutic effect was increased. This relationship reached significance for the serum levels of At (p < 0.05) and a trend for the sum of serum levels of At and Nt (p < 0.1). As expressed by the regression coefficient r2, about 25% to 35% of the variability of therapeutic effect was explained by serum levels. Dichotomized data sets according to limits of final values of HAMD and CGI as well as limits of a therapeutic window of 70 ng/ml and 200 ng/ml (sum of At and Nt) revealed significant differences by means of Fisher's exact test (p < 0.05). Furthermore, increased ratios of serum level of Nt per serum level of At were found to be associated with decreased therapeutic effect. Thus, the present data support the existence of a therapeutic window of serum levels of At in depression. Also taking into account other reports, this therapeutic window can be defined as being between about 70 and 220 ng/ml. The assay of serum levels of At can be used to lower the risk of unsatisfactory therapeutic outcome.

Adult↗
PubMed2003

Predictors of therapeutic effects in amitriptyline treatment--1. Plasma drug levels.

OBJECTIVE: To analyze the spectrum of relationships between clinical effects of amitriptyline (At) treatment after 2 and 4 weeks (wks) and plasma levels of At, nortriptyline (Nt), At+Nt, demethylation rate of At, treatment modalities, age, and gender. METHODS: Patients with major depression (ICD 10: F31-F33) and a HAMD-21 total score of 15-41 received At on a dosage schedule chosen by the doctor for at least 4 wks. Plasma drug levels were assessed at baseline and at wks 2 and 4. RESULTS: Of the 58 patients enrolled in the study, 47 (15males, 32 females) were eligible for statistical analysis. An early response by wk 2 (decrease in HAMD-21 score of at least 50 % from baseline) was observed in 34.0 % of patients, and after 4 wks, the response rate was 63.8 % (males 86.6 %, females 53.1 %). There was a low, negative, and significant correlation between percent reduction in HAMD and steady state At concentration only at wk 2 (n = 47 r Sp. = -0.306 p < 0.05). However, the correlation was dependent on the degree of At demethylation and treatment modalities. A ratio of Nt/At >1 was observed in 23 patients; of these, 11 (47.8 %) were non-responders by wk 4. A low rate of demethylation (Nt/At </= 1) in 24 patients was associated with a lower frequency of non-response (6/24 = 25.0 %). In the latter subgroup, the 2-wk At plasma concentration varied between 20 and 240 ng/ml, and all patients with </= 110 ng At /ml were responders by wk 4. On the other hand, in the Nt/At >1 group, the non-responders were distributed in the whole range of observed At plasma concentrations (20-150 ng/ml). Only in patients with Nt/At </= 1 and constant doses from wk 1 to wk 4 (n = 14) was a strong, linear, and negative correlation between percent reduction in HAMD and plasma At, Nt, or At+Nt concentrations found for the 2-wk data (r Sp. = -0.754, -0.716, and -0.732, respectively), but not after 4 wks. CONCLUSIONS: The frequently assumed dependence of clinical effects on plasma drug levels is not a simple function. There most likely exist different patterns of relationships with partially unknown backgrounds. The ratio Nt/At may become a discriminating variable in future studies on the nature of plasma level-therapeutic effect relationship in At treatment of major depression.

Adult↗
PubMed2005

[Resuscitation after intoxication with amitriptylin].

Intoxications with tricyclic antidepressants are often life threatening situations. In consequence of interference with many organ systems specific treatment consists in transportation to hospital under cardiopulmonary monitoring by physicians. The multiple possibilities of complications require the following treatments: continuous monitoring of the cardiovascular system, gastrolavage, application of carbon through a nasogastric tube, intubation and controlled ventilation in case of coma and continuous stand by for defibrillation. Additionally patients with stable parameters should be monitored in intensive care units because often there are no precursors of cardiac or pulmonary complications. We report the case of a 49-year old women with ingestion of 2500 mg of amitriptyline who suffered from multiple cardiac arrhythmias with following cardiac arrests and who required multiple defibrillations and resuscitation.

Amitriptyline↗
PubMed1989

Noradrenergic output and clinical response in depressed women during amitriptyline therapy.

The measurement of the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in 59 unipolar depressed women before and during administration of 100 mg amitriptyline (AMT) i.m. daily for four weeks showed that the patients could be divided into high or low MHPG excretors. An analysis of the excretion course of MHPG and 3-methoxy-4-hydroxy mandelic acid during therapy showed, in most patients, a lower urinary excretion of both these noradrenaline (NA) metabolites in comparison with basal values. Therapy also decreased plasma noradrenaline concentrations and blood pressure values both at rest and on orthostatic challenge. Available evidence seems to suggest that AMT administration caused a lower overall noradrenergic output that might be partially responsible for a diminished sympathetic nervous activity. The authors were unable to confirm that the baseline MHPG level can predict the clinical response to antidepressant treatment and they found no significant correlations between changes in bio-chemical or physiological variables and drug plasma concentrations or clinical response. The possibility that depressed patients might be grouped according to their different NA metabolism needs to be validated in a larger patient sample.

Adult↗
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↗
PubMed1981

Trazodone and amitriptyline in treatment of depressed inpatients. A double-blind study.

Trazodone (TZ), a 'new generation' antidepressant and amitriptyline (AMT) were administered in a double-blind controlled study to 43 depressed inpatients. The Hamilton Depression Rating Scale (HAM-D), the AMDP-system and the Bf-s self-rating questionnaire were used for documentation of psychopathological changes and autonomic side effects. The Newcastle-Scale for definition of a neurotic and an endogenous subgroup of depression was retrospectively applied. No significant improvement was noticed on the Bf-s self-rating questionnaire in the TZ group as compared to the AMT group (p less than 0.001). The global HAM-D score decreased significantly in the TZ group (p less than 0.05) as well as in the AMT group difference (p less than 0.01) emerged during the trial in favour of AMT. Core symptoms of depression were significantly improved in the AMT group but not in the TZ group: depressed mood (p less than 0.001), psychic anxiety (p less than 0.001) and retardation (p less than 0.05). TZ was faster actin than AMT in controlling agitation. Results of this clinical study demonstrate TZ to have sedative and some anxiolytic properties but only negligible antidepressant efficacy.

Amitriptyline↗
PubMed1998

Is anxious-agitated major depression responsive to fluoxetine? A double-blind comparison with amitriptyline.

Whether fluoxetine (FX) is effective in the treatment of anxious depression is still debated. In the present study, after one week of placebo (single blind), 142 outpatients affected by major depression with relevant anxiety and agitation were randomly assigned (double blind) to either FX (20 mg/day) (n. 67) or amitriptyline (AM) (daily dose: 115+/-39.2mg) (n.75) for a period of 10 weeks. Between groups, the mean score of Hamilton Rating Scale for Depression (HRSD) was significantly different only after 3 weeks of treatment (AM 14.7+/-5.7 vs FX 17.3+/-6.2 (p = 0.02), whereas at the end of the trial it was similar (AM 8.15+/-6.9; FX 8.96+/-6.6). At each visit, no significant difference between groups was found regarding the scores of the HRSD items "psychic anxiety", "somatic anxiety", "agitation". Furthermore, the FIX treatment did not increase the scores of the items "suicide", "psychic anxiety", "somatic anxiety", "agitation" and "insomnia". These findings suggest that patients affected by major depression with anxiety and/or agitation were effectively and safely treated with FX without increasing risks.

Adult↗
PubMed1995

A controlled study of the efficacy and safety of mianserin and amitriptyline in depressive inpatients.

As with other second-generation antidepressants, the antidepressive efficacy of mianserin was investigated in double-blind control group studies, mostly under outpatient conditions. This study tested the antidepressive efficacy and safety of mianserin as compared to amitriptyline in a sample of 51 depressed inpatients suffering from major depression. No statistically significant difference was found with regard to the main efficacy outcome criterion, the HAMD. The tolerability results demonstrated a superiority of mianserin with respect to vegetative symptoms and especially with respect to dryness of the mouth.

Adult↗
PubMed1976

The effect of amitriptyline on forearm blood flow.

The local effect of intra-arterial infusion of amitriptyline (AT) on forearm blood flow was studied in seven healthy subjects. AT was infused at rates of 0.05, 0.10, 0.15, and 0.20 mg-min--1 for periods of 5 min. Forearm blood flow showed a dose-dependent increase when the dose exeeded 0.10 mg-min--1. On the highest dose level the blood flow increased on an average by 73%. No systemic effects, as reflected by changes in heart rate, blood pressure, and blood flow in the contralateral forearm, were observed during the infusion. The present data indicate a dilatating effect of AT on resistance vessels possibly mediated by an alpha-adrenergic blockade.

Adult↗
PubMed1997

Metabolism of amitriptyline with CYP2D6 expressed in a human cell line.

1. Expressed human cytochrome P450 enzyme CPY2D6 was used to metabolize amitriptyline (AMI). It was established that CYP2D6 not only catalyzed ring 10-hydroxylation of AMI, but also mediated its N-demethylation to nortriptyline (NT), as well as the formation of 10-hydroxy-NT from NT. When the metabolism of AMI by CYP2D6 was repeated in the presence of quinidine, none of the metabolites, 10-hydroxy-AMI, NT and 10-hydroxy-NT, was formed. 2. Biochemical parameters of NT formation from AMI were determined, yielding Km = 47.48 +/- 1.32 microM; Vmax = 3.95 +/- 0.11 nmol/h/mg protein. The same parameters were calculated for the formation of 10-hydroxy-AMI (E + Z-isomers) from AMI, yielding Km = 10.70 +/- 0.20 microM; Vmax = 8.99 +/- 0.47 nmol/h/mg protein. 3. The formation of 10-hydroxy-NT from AMI proceeded primarily via NT and to a much lesser extent via 10-hydroxy-AMI. 4. Quantitative analyses of AMI and its metabolites were difficult to reproduce when the metabolites were analysed underivatized. Two derivatization procedures, acetylation and trifluoroacetylation, were employed to improve assay reproducibility.

Acylation↗
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↗
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↗
PubMedDate not supplied

Amitriptyline and procainamide inhibition of cocaine and cocaethylene degradation in human serum in vitro.

Amitriptyline (AMI) and procainamide (PA) have been reported to inhibit the activity of human plasma butyrylcholinesterase, an enzyme important in the metabolic degradation of cocaine (COC) and its ethyl analogue cocaethylene (CE). Because both AMI and PA may be used in the treatment of COC intoxication and abuse, the effect of high pharmacological concentrations of these compounds on the degradation of COC and CE in pooled human serum was studied. AMI (1.8 micromol/L) modestly inhibited the degradation of COC by 4.2% and of CE by 4.0%. PA (42.5 micromol/L) profoundly inhibited degradation of COC by 42.7% and of CE by 47.2%. In contrast, lithium carbonate (1 mmol/L, control) showed no inhibition of degradation of either COC or CE. These results suggest that AMI and PA may prolong the half-life of COC and CE in human serum.

Amitriptyline↗
PubMedDate not supplied

Effective column extraction from decomposed tissue in a suspected overdose case involving maprotiline and amitriptyline.

This paper describes the use of a Celite 560 column extraction technique in the initial separation of drugs from the contents of the skull of a severely decomposed body. Analysis of the extract obtained resulted in the determination of the presence of amitriptyline, and maprotiline and two of its metabolites. As a consequence, the laboratory was able to provide the medical examiner with information concerning an extremely difficult case.

Amitriptyline↗