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PubMed1982

Amitriptyline and nortriptyline excretion in human breast milk.

Simultaneous blood and milk samples were obtained from a 30-year-old woman who was on sustained release amitriptyline, and the concentrations of amitriptyline and the active metabolite, nortriptyline, were estimated by GLC. Serum and milk concentrations were similar with a slight tendency for the amitriptyline concentrations to be higher in milk. Calculation of the transfer of drug from the mother to the baby showed that the baby received an amitriptyline dose which was about one hundredth the dose given to the mother. No active drug could be estimated in the baby's serum and the baby showed no clinical signs which could be drug related.

Adult↗

PubMed1981

Amitriptyline pharmacokinetics. A crossover study with single doses of amitriptyline and nortriptyline.

Six healthy volunteers were given single doses of amitriptyline (AT) and of nortriptyline (NT) separated by at least 10 days. Plasma concentrations of both compounds were measured at intervals for 48 or 72 h. The total areas under the concentration-time curves for the ingested drug were greater for NT, but AT concentrations showed much higher peak values and took more than 12 h to reach the terminal beta phase of elimination. Doses of 50 mg AT produced areas averaging slightly less than half those for 100 mg AT in the same subject, suggesting some saturation of the elimination process. The consumption of a large, fatty meal just before taking the AT tablets had little effect on the plasma drug concentration curves. NT half-lives, measured after ingestion of NT tablets, were used in analysing the production of NT from doses of AT in the same subject. There was a rapid early production, amounting to 30-67% of the total and presumably resulting from the first pass of AT through the liver. NT was then formed continuously at a rate always proportional to the simultaneous rate of AT elimination. The total amount of NT entering the systemic circulation was about one-quarter of the AT dose.

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↗

PubMed1983

The demethylation of amitriptyline: a cross-over study of steady-state plasma levels of amitriptyline and nortriptyline in depressed patients.

Five elderly depressed patients were treated with amitriptyline (AT) and nortriptyline (NT) in turn, in a cross-over design. Steady-state plasma drug levels were compared with those calculated for eight healthy subjects of previous single-dose studies. Plasma clearances were on average about 2.5 times lower in the patients than the healthy subjects, but the ratios of the different reaction rates did not differ significantly between the two groups. The interpretation of the ratio of NT levels during AT treatment and NT treatment, in terms of the fraction of AT that is metabolised by demethylation, is discussed. The ratio of NT level to AT level during AT treatment was particularly variable between individuals. This was apparently due to independent variation in (a) the ratio of plasma clearances of AT and NT and (b) the fraction of AT metabolised to NT.

Aged↗

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↗

PubMed1988

Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-breast differences in two patients.

Flupenthixol (FP), nortriptyline (NT) and zuclopenthixol, (ZCP) were determined in breast milk and plasma from 2 puerperal, lactating women with psychiatric disorders. The milk concentrations were equal to, higher and lower than those in plasma for FP, NT and ZCP, respectively. Variation in milk triglyceride concentration, but not milk pH, could partly explain between-breast differences in the milk concentrations. The study demonstrates the need for appropriate and representative milk sampling procedures. The estimated daily infant exposure averaged 0.5, 2.3 and 0.3% of the corresponding maternal weight related doses of FP, NT and ZCP. FP was also detectable in infant plasma. These drugs are not known to be harmful in small doses to breast-fed infants. However, concern about the effect of dopamine blocking agents on neurobehavioral mechanisms in animals warrants caution. If neuroleptics are required for a long period this risk must be weighed against the benefits of breast-feeding, also considering the psychological effects of the latter.

Adult↗

PubMed1976

Comparison of single dose kinetics of imipramine, nortriptyline and antipyrine in man.

The single dose kinetics of imipramine (IP), nortriptyline (NT), and antipyrine (AP) were compared in 7 healthy subjects. Test doses of AP were given intravenously and test doses of IP and NT were given both orally and by intravenous infusion. The plasma concentration/time curves after intravenous IP and NT were analysed according to a 2-compartment open model. In addition a blood flow independent 'true' clearance was calculated according to a sinusoidal perfusion model. Indirect estimates of hepatic blood flow were obtained from the oral and i.v. plasma concentration/time curves after NT administration. Compared to NT, IP had statistically significant higher clearances, shorter half-lives, and smaller apparent volumes of distribution. There was a significant correlation between apparent volume of distribution (Vdbeta) of IP and NT (n = 5, r = 0.85), but only a weak correlation between the clearance measurements of the two compounds. Systemic clearance of AP and IP showed some positive correlation (n = 7, r = 0.73), whereas there were no significant correlations between AP and NT kinetics. The data indicate that inter- and intraindividual variations in hepatic blood flow may influence the measurements. Other possible sources of variability are individual differences in hepatic extraction kinetics, and differences in binding to blood constituents.

Administration, Oral↗

PubMed1990

Aspects of amitriptyline and nortriptyline plasma levels monitoring in depression.

Fifty-nine depressed female inpatients were treated with 100 mg amitriptyline (AMT) IM for 4 weeks. Depression ratings and determinations of the parent drug and nortriptyline (NT) were performed weekly. No direct relationship between plasma AMT + NT concentrations and therapeutic response was apparent, but beneficial therapeutic responses and significantly lower side-effect scores were more frequently noted in subjects with concentrations in the 100-200 ng/ml range. AMT + NT concentrations were significantly correlated with age. No significant difference was found in the number of responders between younger and older subjects with two clinical improvement criteria; however, a significant difference emerged when a third more restrictive clinical outcome criterion was adopted. The implications of the present findings for patient treatment and for the interpretation of previous studies are discussed. The data collected point to a possible usefulness of monitoring AMT and NT plasma levels, even if further investigations are needed.

Adult↗

PubMed1996

Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype.

The relationship between the CYP2D6 genotype and the steady state plasma levels of nortriptyline (NT), its main active metabolite 10-hydroxynortriptyline (10-OH-NT) and the NT/10-OH-NT ratio were studied in 21 Caucasian depressed patients treated with 100-150 mg NT daily. The patients had participated in a previously published study investigating the role of NT and 10-OH-NT for the therapeutic effect of NT, and the plasma level data were from that study. In the present follow-up study, the patients were genotyped with respect to the polymorphic CYP2D6 by allele-specific PCR amplification and EcoRI RFLP. One poor metabolizer (PM) was identified and she had the highest plasma concentration of NT. Among the 20 extensive metabolizers (EM), the genotype (homozygous versus heterozygous EM) alone was not found to explain the variance in dose-corrected NT concentrations, but contributed significantly when gender was also taken into account. Together, these factors accounted for 59% of the variability in NT levels. Female patients had higher plasma levels of NT than male patients. 10-OH-NT levels were influenced by genotype, and NT/10-OH-NT ratio by genotype and gender. The present follow-up study confirms a relationship between the CYP2D6 genotype and the plasma levels of NT and its active metabolite. Identification of PM by genotyping should be of value for the prediction of the plasma levels and, consequently, the lower than average dose of NT required for optimal therapy. Also among EM, the genotype contributes to the variability in NT and 10-OH-NT levels but alone is of limited practical value for the prediction of optimal dosage.

Adult↗

PubMed1990

Self-inhibiting action of nortriptyline's anti-immobility effect at high plasma and brain levels in mice.

Animals were treated acutely with 0, 2.5, 5, 10, 20 and 40 mg/kg nortriptyline (NT) 30 min before the tail suspension test (TST). They were sacrificed after test for evaluation of plasma and brain levels of NT. The anti-immobility effect increased with increasing doses and concentrations of the drug, reaching statistical significance (P less than 0.01, Dunnett test) at a dose of 20 mg/kg, 865 ng/ml in plasma and 11 micrograms/g in brain tissue. The anti-immobility effect was, however, blocked with the highest, non-toxic, concentrations. Results seem to indicate a biphasic curvilinear relationship between plasma and brain levels of NT and behaviour in mice.

Animals↗

PubMedDate not supplied

Clinical response and plasma concentrations of amitriptyline and its metabolite-nortriptyline in depressive patients.

Although many attempts have been made, to date no convincing evidence exists of a relationship between plasma concentrations of amitriptyline (AT), its active metabolite nortriptyline (NT) and clinical response. Fifteen patients with primary depression (according to DSM-IV) were divided in two groups according to given doses: (I) 6 patients received 3 x 50 mg of AT daily; and (II) 9 patients received 3 x 25 mg of AT daily, for 6 weeks. The clinical status was determined with Hamilton Depression Rating Scale. Both investigated doses were therapeutically effective. AT and NT plasma concentrations were assayed by high performance liquid chromatography. Following administration of 3 x 50 mg of AT daily, the correlation of concentrations of AT, NT, total AT + NT and clinical response were rAT = -0.702 (P < 0.1), rNT = -0.761 (P < 0.1), rAT + NT = -0.741 (P < 0.1). The linear and very high correlation were also present with concentrations of AT, NT, total AT + NT and clinical response in depressive patients on 3 x 25 mg AT daily: rAT = -0.785 (P < 0.02), rNT = -0.811 (P < 0.01), rAT + NT = -0.848 (P < 0.01). Our results support a high correlation between AT/NT plasma concentrations and clinical response indicating that therapeutic monitoring of AT and its metabolite, NT, can provide eventual clinical response.

Adult↗

PubMed2001

Transplacental transfer of amitriptyline and nortriptyline in isolated perfused human placenta.

RATIONALE: Although tricyclic antidepressants (TCAs) have gained wide acceptance for use in the treatment of depression in pregnant women, their pharmacokinetics during pregnancy have been poorly characterized. The aim of the present study was to investigate the transplacental transfer of amitriptyline (AMI) and its main active metabolite nortriptyline (NOR) in isolated perfused human placenta. METHODS: Nine term human placentae were obtained immediately after delivery with maternal consent and a 2-h non-recirculating perfusion of a single placental cotyledon was performed. AMI (200 ng/ml) and NOR (150 ng/ml), with antipyrine as a reference compound, were added to the maternal reservoir and their appearance to the fetal circulation was followed for 2 h. AMI and NOR concentrations were measured by high performance liquid chromatography (HPLC) and antipyrine concentrations spectrophotometrically. RESULTS: The mean (SD) transplacental transfers (TPT(SS)%) for AMI and NOR were 8.2 (2.3)% and 6.5 (1.8)%, respectively, calculated as the ratio between the steady-state concentrations in fetal venous and maternal arterial sides. The TPTs of AMI and NOR were 81% and 62% of the freely diffusable antipyrine. The absolute fraction of the dose that crossed the placenta (TPT(A)) was moderately, but significantly higher for AMI (7.7%) than for NOR (5.7%) (P=0.037). In all perfusions, steady state at the fetal side was reached by 30 min for AMI and by 50 min for NOR in the fetal side. The viability of the placentae was retained during the 2-h perfusion, as evidenced by unchanged pH of the perfusate and by stable perfusion pressures in fetal artery and stable antipyrine transfer. CONCLUSIONS: Both AMI and NOR cross the human placenta. However, the fetal exposure with NOR may be somewhat smaller compared with AMI, probably due to the higher lipophilicity of AMI.

Adult↗

PubMed1984

The complex binding of tricyclic antidepressants to rat brain: the case of nortriptyline.

[3H]Nortriptyline (NT) binding to rat brain sections was characterized using saturation and competition experiments, quantitative autoradiographic localization and monoaminergic lesions. [3H]NT binding exhibits a saturable component in the nM range (high affinity binding). Final saturation is reached only in micromolar concentrations (low affinity binding). The high affinity binding sites of [3H]NT appear in areas rich in noradrenergic and serotonergic terminals, and are decreased by 6-OHDA and 5,7-DHT lesions, to an extent depending on the brain region and the relative density of noradrenergic and serotonergic terminals there. We conclude that [3H]NT binds with high affinity to both noradrenergic and serotonergic nerve terminals, and with low affinity to other yet uncharacterized entities. This complex binding pattern is compatible with the multiplicity of biochemical, physiological and behavioral effects of NT and tricyclic antidepressants in general.

Animals↗

PubMed1984

Affinity of nortriptyline to muscarinic receptors in the bladder and ileum of man and guinea-pig.

The antagonism by nortriptyline of carbachol- or urecholine-induced contractions was studied in strips of ileum and bladder derived from man and guinea-pig. Analyses of the results by the dose ratio method (Schild plots) showed significant differences in the affinities of the relevant muscarinic receptors to the antagonist: The Ki values in microM were as follows: Human ileum, 0.938; human bladder, 0.298; guinea-pig ileum, 0.159; guinea-pig bladder, 0.333 and 0.453. In man, the higher affinity of the drug to the receptors in the bladder than to those in the ileum may be of consequence in its therapeutic application as an antienuretic agent.

Animals↗

PubMed1983

Correlation between nortriptyline and debrisoquine hydroxylation in the human liver.

The benzylic hydroxylation of nortriptyline (NT) and debrisoquine (D) by isolated human liver microsomes from eight subjects was studied. There was a strong correlation between the 10-hydroxylation of NT and the 4-hydroxylation of D (r = 0.96). The ability to hydroxylate D was also measured in vivo as the ratio between D and 4-OH-D in urine after oral administration of the drug to four subjects. This estimate of hydroxylation capacity agreed with the in vitro measurements. Liver microsomes from a subject defined as a poor in vivo oxidizer of D hydroxylated NT and D unusually slowly. Separation of microsomal proteins by SDS-gel electrophoresis indicated a relative lack of a cytochrome P-450 isozyme with a molecular weight of 54,500 in the liver from the poor oxidizer.

Adult↗

PubMed1984

Weak binding of 10-hydroxymetabolites of nortriptyline to rat brain muscarinic acetylcholine receptors.

The relative affinities of nortriptyline (NT) and its 10-hydroxymetabolites to rat brain muscarinic acetylcholine receptors have been determined by competition with 3H-quinuclidinyl benzilate binding. It is shown that the major NT metabolite, E-10-OH-NT, has only 1/18 the affinity of NT for the muscarinic receptor. Since this metabolite is equipotent to NT in inhibiting neuronal noradrenaline uptake, it is suggested that it might be of clinical value as an antidepressant by virtue of having less anticholinergic side-effects than NT itself.

Amitriptyline↗

PubMed1981

Effects of nortriptyline treatment on learned helplessness in the rat.

Using an escape delay procedure previously shown to elicit behavioral deficits in mice exposed to uncontrollable shock, rats treated with inescapable but not escapable shock or no shock displayed comparable interference effects when tested in a two-way shuttle box 24 hr later. Treatment with 12.5 mg/kg nortriptyline for 4 or 6 days counteracted the escape deficits produced by inescapable shock while the 0 or 2 day administration regimens were without any appreciable effect. The finding that interference effects produced by inescapable shock were sensitive to sub-acute but not acute drug administration supports the utility of the learned helplessness model in evaluating potential antidepressant agents in experimental animals.

Animals↗

PubMed1986

Cardiac antiarrhythmic effect of nortriptyline.

With a quinidine-like cardiac action, the tricyclic antidepressant drugs, imipramine in particular, have been proposed as potentially antiarrhythmic agents. The antiarrhythmic activity of nortriptyline is described in a depressed patient with premature ventricular complexes, and the basis for this activity is discussed.

Anti-Arrhythmia Agents↗