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PubMed1986

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes.

The metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), chlorimipramine (CMI) and some of their metabolites was studied in vitro in isolated liver microsomes of female Spraque-Dawley rats. Nine metabolites of AMI, seven metabolites of IMI, and 11 metabolites of CMI were quantitatively determined with high-performance liquid chromatography. The main metabolic reactions, mediated by an NADPH generating system, were hydroxylation, demethylation, and N-oxidation. The ratio of these reactions was different for the three drugs. AMI was hydroxylated more than CMI and CMI more than IMI. The order for demethylation was CMI greater than AMI = IMI, the order for N-oxidation IMI greater than CMI less than or equal to AMI. The substrate dependence of metabolism was investigated. Demethylation and N-oxidation increased proportionally to increasing substrate concentrations, whereas formation of hydroxylated metabolites became saturated (in the concentration range of 10(-6)-10(-5) M). The in vitro metabolism was compared with the in vivo metabolism in humans, reflected by the plasma concentrations of these drugs and their metabolites. A good agreement in metabolic pathways was found.

Amitriptyline↗
PubMed1986

Amitriptyline and oxaprotiline in the treatment of hospitalized depressive patients. Clinical aspects, psychophysiology, and drug plasma levels.

Amitriptyline (AT) and the noradrenaline reuptake inhibiting antidepressant oxaprotiline (OT = hydroxymaprotiline) were compared in 59 primary depressive inpatients in a 4-week double blind parallel group design. In the Hamilton Depression Rating Scale and 2 self-rating scales AT proved to be more efficient than OT, mainly with respect to disturbances of appetite and sleep. Agitated patients receiving OT needed more additional tranquilizing medication. The number of side-effects did not differ. Both drugs increased heart rate and skin resistance level (SRL) to about the same degree and did not influence the number of spontaneous fluctuations of SRL, habituation of SRL orienting responses (OR), frequencies of respiration and blinking. Salivation was temporarily more impaired by AT. All physiological variables differed between patients and 30 healthy controls during the whole 4-week trial. Clinical outcome showed a linear relation to OT plasma levels. For AT a therapeutic window was confirmed for concentrations of AT and its metabolite nortriptyline between 125 and 200 ng/ml. Patients whose SRL-OR habituated rapidly had a better outcome than slow habituators. Urinary excretion of 3-methoxy-4-hydroxyphenylglycol was lower in patients than in controls but could not predict outcome with either drug.

Amitriptyline↗
PubMed1976

Autonomic actions and interactions of mianserin hydrochloride (Org. GB 94) and amitriptyline in patients with depressive illness.

The clinical pharmacology of mianserin hydrochloride was studied in patients suffering from a primary depressive illness after steady-state plasma concentration of the drug had been achieved. The results were compared with those found with amitriptyline in both open and double-blind studies. The two drugs are equally effective in their antidepressive effect. Mianserin hydrochloride appears to be free of anticholinergic effects as assessed by the measurement of salivary volume, pupil diameter and the interactions with guanethidine and thymoxamine on the pupil. No peripheral adrenergic interaction as studied by the tyramine dose-pressor-response test were observed in patients treated with mianserin hydrochloride (20 mg three times daily).

Amitriptyline↗
PubMed1985

Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients.

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n = 17) and amitriptyline (AT, n = 16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiles for uptake blockade and anticholinergic potency for these two compounds.

Adult↗
PubMed1979

Urinary 4-hydroxy-3-methoxyphenylglycol is not a predictor for clinical response to amitriptyline in depressive illness.

The urinary excretion of 4-hydroxy-3-methoxyphenylglycol was compared in a group of 23 depressive patients and 27 control subjects of similar age. There was no difference between patients and controls although female controls excreted less than males. After 6 weeks' treatment with 150 mg daily of amitriptyline there was no correlation between therapeutic response and pretreatment urinary excretion value.

Amitriptyline↗
PubMed1983

Tricyclic plasma levels in depressed outpatients treated with amitriptyline.

Seventy-four patients were treated with 150 mg/day amitriptyline (AT) to determine possible correlations between clinical improvement, demographic variables, and AT and nortriptyline (NT) plasma levels. Plasma level determinations after 2 and 6 weeks of treatment revealed that moderately significant correlations existed between AT plasma levels and clinical improvement, dosage intake, age, weight, sex, and coffee intake. Some of these findings were more pronounced after 2, and some after 6 weeks of treatment.

Amitriptyline↗
PubMed1984

The effect of aging on the positive chronotropic response to amitriptyline.

Amitriptyline (AT) increases sinus heart rate (SHR) due to inhibition of the reuptake of norepinephrine in combination with an antimuscarinic blockade of cardiac vagal inhibition. After 150 mg/day AT for 28 days, the change in SHR was negatively correlated with age in 42 depressed patients who were 18-85 years of age. This finding is consistent with observations that the tachycardic response to antimuscarinics and catecholamines decreases with aging.

Adult↗
PubMed1984

Evaluation of the levels of free and total amitriptyline and metabolites in the plasma and brain of the rat after long-term administration of doses used in receptor studies.

This study was conducted in order to investigate the level of amitriptyline (AT) and its metabolites. Three separate experiments were carried out. In two of these experiments, rats were treated over 7 days with IP doses of AT (10 mg/kg in experiment A and 2 X 20 mg/kg in experiment C). The rats were sacrificed either 2 (experiment C) or 12 h (experiments A and C) after the last dose. In experiment B, rats were sacrificed 2 or 12 h after a single dose of 20 mg/kg AT. The results of these experiments showed the following: in experiment A only AT was measurable in the brain and in the plasma, in contrast to experiments B and C, where NT and the hydroxylated metabolites AT-OH and NT-OH reached significant levels in the plasma and in the brain. The concentrations of AT-OH, NT-OH, and NT (12-h values) that were found in the brain are probably not pharmacologically relevant. The 12-h plasma values of all compounds tested were, even with the highest dose, lower than those expected to be clinically effective in man. Our results suggest that AT, at higher doses, may induce its own metabolism. The free plasma levels of this drug and its metabolites are higher in man than in the rat. The possible implications of these results in the use of antidepressants in the treatment of depression are discussed.

Amitriptyline↗
PubMed1984

Single-dose single-point method in amitriptyline therapy.

Twenty-one depressed patients participated in a study that assessed the predictability of amitriptyline (AT) dosage based on plasma drug concentrations after a single dose. In 11 patients maintained on a fixed dose regimen, the 18-h single-dose level was confirmed to be predictive of steady-state levels. The dose for the next 10 patients was derived from their 18-h level aiming to attain steady-state levels of 200 ng/ml. The patients achieved a mean steady-state level of 213 ng/ml with 80% attaining therapeutic levels. All the patients improved within 2 weeks. These preliminary results suggest that dose prediction based on a single-dose TCA level is reliable and beneficial.

Adult↗
PubMed1981

Binding of amitriptyline and nortriptyline in plasma determined from their equilibrium distributions between red cells and plasma, and between red cells and buffer solution.

In a new method for the measurement of plasma binding, amitriptyline (AT) and nortriptyline (NT) were allowed to reach equilibrium distribution between the cells and plasma of whole blood. A separate sample of the cells was equilibrated with a buffer solution containing the drugs. From the two distribution ratios for each drug, the fraction free in the plasma was calculated. Equilibria were achieved rapidly, avoiding denaturation of binding proteins. The pH was adequately controlled and the composition of the plasma was not altered by the experimental procedures. Large volumes of buffer solution gave amounts of free drug readily measurable by gas chromatography. Duplicate determinations showed coefficients of variation of 6% and 4.8% respectively for the free fractions of AT and NT in a given plasma sample. In 51 subjects the mean percentage of AT free in plasma was 4.31 +/- 0.59 SD and, of NT, 8.59 +/- 0.86. Binding was independent of drug concentration in the therapeutic range and did not differ between males and females nor between patients and normal subjects. It increased slightly with age. It was not affected by chylomicrons in the blood.

Amitriptyline↗
PubMed1982

Do urinary MHPG and plasma drug levels correlate with response to amitriptyline therapy?

Twenty-nine inpatients with primary affective disorder were treated with 150 mg amitriptyline (AT) daily for 28 days. Pretreatment urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in two or three 24-h urine samples. Plasma levels of AT and nortriptyline (NT) were determined after 14, 21, and 28 days of treatment. MHPG excretion was significantly correlated with clinical response to treatment. Responders defined by two different methods showed higher pretreatment MHPG excretion than nonresponders. Correspondingly, high MHPG excretors (median split) showed significantly more improvement than low excretors. These relationships were even more apparent when possibly incomplete urine samples (creatinine excretion below 1000 mg/24h) were excluded. The high and low MHPG subgroups did not significantly differ from each other in their plasma levels of AT, NT, or AT plus NT. A significant rank correlation between clinical response and plasma levels of AT and/or NT did not exist, but there was a trend towards lower levels in responders.

Adult↗
PubMed1982

Antidepressive effect and pharmacokinetics of amitriptyline with consideration of unbound drug and 10-hydroxynortriptyline plasma levels.

In 27 inpatients with primary affective disorder the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured prior to a 4-week treatment with 150 mg amitriptyline (AT)/day. Ratings according to the Hamilton depression scale were performed before therapy and repeated after 2 and 4 weeks. Plasma levels of AT, nortriptyline (NT), and E-10-hydroxynortriptyline (OHNT) were assayed weekly, and binding of AT to plasma proteins was determined in one sample. Better therapeutic results were obtained at intermediate, as compared to low and high concentrations of AT or AT plus NT. Independent evaluation of AT and metabolite levels revealed that patients with AT of 50--125 ng/ml responded particularly well when NT did not exceed 95 ng/ml or when NT plus OHNT was below 150 ng/ml. Outside this "therapeutic window' the outcome was markedly poorer. Interindividual variation of AT binding was much smaller than variation of total concentrations. Evaluation of free, instead of total levels did not help to clarify the relationship between clinical and pharmacokinetic variables. Plasma levels within the optimal ranges were found in more patients with high than with low MHPG excretion. The free fraction of OHNT in plasma of healthy subjects was about 35%.

Adult↗
PubMed1982

The effect of d-amphetamine and amitriptyline administered to pregnant rats on the locomotor activity and neurotransmitters of the offspring.

d-Amphetamine and amitriptyline (AT) were administered daily to female rats from day 7 of pregnancy until birth of the litters. Changes in the concentration of the biogenic amines, some of their metabolites, GABA, and the activities of glutamate decarboxylase, acetylcholinesterase (AChE), and choline acetyltransferase were determined in the whole brain of the offspring. The offspring of the amphetamine-treated rats showed a marked increase in serotonin concentration and that of its metabolite on postnatal day 1. Changes in the concentration of GABA were apparent on days 15 and 21 and were inversely correlated with changes in the activity of the synthesizing enzyme: Choline acetyltransferase and AChE activities were also increased at this time. Changes in neurotransmitter metabolism were not so evident in the offspring of rats treated with AT. The locomotor activity of the 8-, 15-, and 21-day offspring was also assessed. The offspring of the amphetamine-treated rats showed enhanced locomotor activity initially, but the activity decreased relative to the age-matched controls in the 21-day group. Offspring from the AT-treated group showed reduced locomotor activity.

Amitriptyline↗
PubMed1979

Plasma tricyclic drug levels in amitriptyline-treated depressed patients.

In a double-blind phenelzine controlled clinical trial, 49 depressed outpatients were treated with a fixed dose of amitriptyline (AMI) 150 mg/day for 6 weeks. No significant relationships were found between steady-state plasma levels of AMI and its metabolite, nortriptyline, at 4 weeks and therapeutic response at 6 weeks or side effects. In the patient subgroup with more severe endogenous symptoms, there was a general trend for a weak positive association between AMI plasma levels and clinical improvement. Plasma tricyclic determinations appear to have little if any predictive value for antidepressant effect in outpatients treated with AMI.

Adult↗
PubMed1983

Ethanol effects on brain concentrations of amitriptyline and the relationship to psychomotor function.

The effect of amitriptyline (AMI), ethanol (ETOH), and ETOH followed by AMI on both general activity (open field) and motor performance (two rotorod tasks) was tested in reference to a saline-injected control. The combination (ETOH plus AMI) produced greater impairment on all three tasks than did either drug alone. ETOH pretreatment also produced a 223% increase in the total tricyclic antidepressant (TCA) brain concentration. The decrement in motor performance was logarithmically related to total TCA brain concentrations in both animals treated with AMI alone and those pretreated with ETOH prior to AMI. The concentration which consistently produced behavioral impairment was similar to those previously reported to cause cognitive and electroencephalographic dysfunction in humans.

Amitriptyline↗
PubMed1983

The demethylation of amitriptyline administered by oral and intramuscular routes.

A single intramuscular (IM) dose of 50 mg amitriptyline (AT) was given to each of two healthy subjects who had previously taken three oral doses of AT tablets. The concentration-time curves of plasma nortriptyline (NT) arising from IM AT were fitted by computer to an equation based on the assumptions that NT is produced at a rate proportional to plasma AT concentration and is eliminated at a rate proportional to plasma NT concentration. The total amount of systemic NT produced was approximately equal for IM and oral AT doses, suggesting that the hepatic elimination of a given quantity of AT produces a constant amount of systemic NT, whether the AT is metabolised in the first pass or from the systemic circulation. This conclusion is supported by analysis of the time course of plasma NT concentration arising from oral AT doses. A large early production had previously been demonstrated and attributed to first-pass metabolism. The proportion of each oral AT dose eliminated in the first pass could now be estimated. Values ranged from 51% to 70% and were approximately equal to the proportion of the total NT apparently formed in the first pass.

Administration, Oral↗
PubMed1982

A liquid chromatographic method for quantitating amitriptyline in brain tissue.

A previously reported method for measuring tricyclic antidepressants (TCA) in plasma was modified to measure TCA, specifically amitriptyline (AMI) and nortriptyline (NOR) in rat brain tissue. Brains obtained from drug-free and AMI-treated rats were extracted and assayed using a Waters high-performance liquid chromatograph. Drug-free brain tissue contained no substances which interfered with the assay of these TCAs. Drug recovery averaged 90 +/- 3.4% (mean +/- SEM). Seven intra-run assays of a spiked brain tissue sample yielded coefficients of variation of 2.7% for AMI and 1.8% for NOR. Seven inter-run assays of the same sample varied 4.2% for AMI and 3.5% for NOR. Five separate assays of a brain homogenate sample spiked with 50 ng/ml of drug yielded values of 50 +/- 2.1 SEM ng/ml for AMI and 54 +/- 1.1 SEM ng/ml for NOR. Standard curves were linear when constructed from samples in a concentration range of 250--3,000 ng/g wet weight tissue (r = 0.96, P less than 0.001).

Amitriptyline↗
PubMed1980

The contribution of alpha 1-acid glycoprotein, lipoproteins, and albumin to the plasma binding of perazine, amitriptyline, and nortriptyline in healthy man.

Parameters for the binding of perazine (PER), amitriptyline (AT) and nortriptyline (NT) to plasma and to single plasma proteins were determined by equilibrium dialysis. The highest affinity (K at least 10(5) M-1) and lowest capacity (first site 1 mol/mol) towards all three drugs was exhibited by alpha 1-acid glycoprotein (alpha 1-AGP). From the parameters, alpha 1-AGP was estimated to contribute 43% to total binding of PER and 49 and 31%, respectively, to AT and NT binding in samples with normal protein concentrations. Fractions bound to total lipoproteins would amount to 32% (PER), 40 (AT) and 52% (NT), respectively, while the contribution of albumin would range from 11% (AT) to 25% (PER). The extent of the binding to plasma was compared with that to single proteins and their mixtures. Binding to combinations of alpha 1-AGP, lipoproteins and albumin exceeded that to plasma with PER but not with AT and NT. This leads to the assumption that additional plasma constituents interfere with PER binding.

Amitriptyline↗