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PubMed2005

Influence of P-glycoprotein inhibition on the distribution of the tricyclic antidepressant nortriptyline over the blood-brain barrier.

The distribution of the antidepressant drug nortriptyline (NT) and its main metabolite E-10-hydroxy-nortriptyline (E-10-OH-NT) across the blood-brain barrier was considered in relation to inhibition of the multidrug transporter P-glycoprotein (P-gp). Rats received NT in doses of 25 mg/kg orally, 10 mg/kg i.p. or 25 mg/kg i.p. Half the rats were treated with the P-glycoprotein inhibitor cyclosporine A (CsA) (200 mg/kg) 2 h prior to NT administration, and the other half served as a control group. NT and the metabolite were extracted from brain and serum by liquid-liquid extraction and analysed by HPLC with UV-detection. The brain to serum ratio of NT was increased in the CsA treated groups (22.3-26.8) compared with the control groups (16.5-22.7), the difference being statistically significant in two of the three experiments (p<0.05). Increased brain-serum ratios were also found for E-10-OH-NT, but the differences were not statistically significant. These results suggest that inhibition of P-gp by CsA increases the accumulation of NT in the brain. Administration of the antipsychotic drug risperidone (0.5 mg/kg s.c.), which is a P-gp substrate, instead of CsA did not exert any measurable influence on the blood-brain ratio of NT concentrations. In conclusion, the results show that drug-drug interaction at P-gp may influence the intracerebral NT concentration, but apparently, a major inhibition of P-gp is necessary to attain a measurable effect.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1975

Comparison of observed and predicted bioavailability of nortriptyline in humans following oral administration.

The first-pass equation based on the dose, hepatic blood flow, and total area under the plasma level-time curve after oral administration was used retrospectively to predict the bioavailability of nortriptyline after oral administration of 1 mg/kg-single oral doses to monozygotic and dizygotic twin pairs. The predicted values of bioavailability ranged from 45 to 85%, consistent with experimentally derived estimates of nortriptyline availability.

Administration, Oral↗
PubMed1977

Radiochemical GLC assay for nortriptyline in human plasma.

A novel method was developed for the assay of nortriptyline in plasma. After nortriptyline was extracted, it was acetylated with 3H-acetic anhydride; the quantity of 3H-acetylnortriptyline in the extract was determined by radiochemical GLC. The method is capable of assaying 5 ng of nortriptyline/ml of plasma. The instrumentation was assembled from commercially available components.

Acetylation↗
PubMed1977

First pass hydroxylation of nortriptyline: concentrations of parent drug and major metabolites in plasma.

Nortriptyline was given orally and intramuscularly to six depressed patients. Plasma concentrations of parent drug and the unconjugated and conjugated principal metabolite, 10-hydroxynortriptyline, were determined by mass fragmentography. There was a significant decrease in the area under the nortriptyling plasma concentration- time curve after the oral route of administration, whilst the elimination rate was unchanged. With the oral dose, plasma concentrations of the metabolites were higher and peaked earlier than after intramuscular administration, whilst the opposite was true for the parent compound. This proves that the difference in bioavailability between the two routes of administration was due to first pass metabolism. As determined from the ratio between corresponding areas, the relative bioavailability of the oral dose was 66 +-21 S.D. per cent. This fraction is higher than that reported previously when intravenous nortriptyline was used as the reference dosage form.

Administration, Oral↗
PubMed1981

Simultaneous liquid chromatographic analysis of amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and nordoxepin.

A simultaneous method for the therapeutic monitoring of amitriptyline, doxepin, imipramine, and their active demethylated metabolites nortriptyline, nordoxepin, and desipramine, respectively, in plasma or serum by reversed-phase liquid chromatography (RPLC) is presented. The drugs and the internal standard (loxapine) are first extracted from 2 ml of serum into butylchloride at pH 14, and then back extracted into 200 microliter of 0.025 mol/l hydrochloric acid. An aliquot of the aqueous acid phase is injected into the chromatograph and eluted with acetonitrile-phosphate buffer (21: 79, by vol.) containing 0.6 nl of n-nonylamine per liter of phosphate buffer. The drugs are eluted in a total chromatographic time of approximately 13 min at ambient temperature and detected at 200 nm. A sensitivity of 5 microgram/l of serum for each drug is obtained. Recoveries for these drugs ranged from 77% to 103%; and the coefficient of variation (day-to-day) ranged from 4.2 to 7.8. Of 35 basic or neutral drugs tested for possible interference, only propoxyphene interferes with the analysis of nortriptyline.

Amitriptyline↗
PubMed1993

Immunoassay reagents for psychoactive drugs. I. The method for the development of antibodies specific to amitriptyline and nortriptyline.

Amitriptyline and nortriptyline were structurally modified by the attachment of spacer arms to the aromatic ring which were subsequently attached to bovine serum albumin (BSA). Rabbits inoculated with these conjugates yielded polyclonal antisera with high selectivity and good titers. This approach required novel spacer arms and new conjugation methods. The antisera produced were characterized with respect to their cross-reactivity with amitriptyline, nortriptyline and their hydroxy metabolites as well as selected structurally related compounds.

Amitriptyline↗
PubMed1975

Nortriptyline hydrochloride in urology.

Forty female patients suffering for long periods from frequency, urgency, and dysuria without any definite organic cause received nortriptyline chloride for three weeks. In 75 percent there was either considerable improvement or total disappearance of urinary complaints. At the same time the in vitro effects of the drug were tested using the isometric muscle contraction technique. Nortriptyline was found to have anticholinergic properties. The importance of this effect in the clinical study and the possible mode of action of the drug are discussed.

Acetylcholine↗
PubMed1984

3H-imipramine binding sites in brain down-regulated by chronic nortriptyline and haloperidol but not mianserin treatment.

Specific binding of 3H-imipramine to membrane preparations from the cerebral cortex and hippocampus was measured in rats given nortriptyline (10 mg/kg/day), mianserin (10 mg/kg/day), haloperidol (1 mg/kg/day), or saline for 21 days and killed 48 hours after the last injection. Chronic treatment with nortriptyline resulted in a significant decrease in density (Bmax) of 3H-imipramine binding sites in the hippocampus but not in cerebral cortex without significant changes in binding affinity (Kd). Mianserin treatment failed to alter Bmax and Kd of specific 3H-imipramine binding in either of the two brain regions. Repeated administration of haloperidol also produced a lowering in the number of 3H-imipramine binding sites (Bmax) in the hippocampus. The results indicate that the ability of tricyclic antidepressants to down-regulate 3H-imipramine recognition sites in the brain is not shared by nontricylic antidepressants such as mianserin. The observation that down-regulation of binding can also be produced by a typical antipsychotic drug, haloperidol, suggests that this phenomenon may not be related to the mode of therapeutic effect of antidepressants.

Animals↗
PubMed1984

Effects of lithium, nortriptyline and dexamethasone on insulin sensitivity.

The effects of lithium, dexamethasone, nortriptyline and their combinations on insulin sensitivity, expressed as a drop of plasma glucose in response to insulin challenge, were investigated in healthy volunteers. Short-term (three weeks) lithium treatment did not appear to exert any influence on the insulin sensitivity. Dexamethasone administered alone (2 mg given 57 hours prior to the test) had no effect on the insulin sensitivity of drug-free healthy subjects. However, after three weeks of lithium treatment the dexamethasone premedication resulted in slight flattening of glucose response to insulin in the same persons. Nortriptyline administered for three weeks to healthy volunteers, pretreated with dexamethasone, increased insulin sensitivity. These findings may have clinical implications regarding the treatment of depressed diabetic patients, and may provide information about the regulation of insulin sensitivity.

Adult↗
PubMed1987

Effect of citalopram, amineptine, imipramine and nortriptyline on stress-induced (footshock) analgesia in rats.

The influence of the oral administration of different doses of citalopram (5, 15 and 45 mg/kg), imipramine (15, 30, 45 and 60 mg/kg), nortriptyline (15, 45 and 60 mg/kg) and amineptine (45 mg/kg) on stress-induced analgesia has been studied in anaesthetized rats. None of the administered antidepressants seem to have appreciable analgesic activity when analgesia is tested by the tail-immersion method. Citalopram, imipramine and nortriptyline, but not amineptine, increase the analgesia induced by inescapable footshock delivered continuously for 2 min to rats. Citalopram is the most potent drug. Our results support the suggested importance of 5-HT and noradrenaline terminals, but not those of dopamine, in the mediation of the stress-induced analgesia and seem to support the hypothesis that the analgesic activity of antidepressants is partially related to their modulating effects on the endogenously released opioid peptides involved in the endogenous pain inhibitory systems.

Animals↗
PubMed2005

Separation mechanism of nortriptyline and amytriptyline in RPLC.

The single and the competitive equilibrium isotherms of nortriptyline and amytriptyline were acquired by frontal analysis (FA) on the C18- bonded discovery column, using a 28/72 (v/v) mixture of acetonitrile and water buffered with phosphate (20 mM, pH 2.70). The adsorption energy distributions (AED) of each compound were calculated from the raw adsorption data. Both the fitting of the adsorption data using multi-linear regression analysis and the AEDs are consistent with a trimodal isotherm model. The single-component isotherm data fit well to the tri-Langmuir isotherm model. The extension to a competitive two-component tri-Langmuir isotherm model based on the best parameters of the single-component isotherms does not account well for the breakthrough curves nor for the overloaded band profiles measured for mixtures of nortriptyline and amytriptyline. However, it was possible to derive adjusted parameters of a competitive tri-Langmuir model based on the fitting of the adsorption data obtained for these mixtures. A very good agreement was then found between the calculated and the experimental overloaded band profiles of all the mixtures injected.

Adsorption↗
PubMed2005

Amitriptyline and nortriptyline serum determination by micellar liquid chromatography.

INTRODUCTION: Amitriptyline and nortriptyline are tricyclic antidepressants which act by enhancing the actions of norepinephrine and serotonin caused by blocking the re-uptake of various neurotransmitters at the neuronal membrane. A micellar liquid chromatographic procedure was developed to determine these drugs in serum samples for use in clinical monitoring. METHODS: The chromatographic determination of these highly hydrophobic substances was carried out using a 0.15 M SDS-6% (v/v) pentanol buffered at pH 7, in a C18 column, and electrochemical detection at 650 mV. The flow-rate was 1.5 mL/min. The analysis time was 14 min. RESULTS: The limits of detection (ng/mL) in serum were 0.25 and 0.31 for amitriptyline and nortriptyline, respectively. Repeatability and intermediate precision were evaluated at three different concentrations in serum samples. DISCUSSION: Untreated serum samples were injected directly into the HPLC system after filtration, leading to be a simple procedure that can be applied in routine analyses for Therapeutic Drug Monitoring.

Amitriptyline↗
PubMedDate not supplied

Use of charge-transfer complex formation for the spectrophotometric determination of nortriptyline.

Three simple and selective methods are proposed for the determination of nortriptyline hydrochloride in bulk form and in tablets. The first two methods are based on the formation of charge-transfer complexes between the drug base as a n-donor and quinhydrone or p-chloranil as pi-acceptor. The products exhibit absorption maxima at 497 and 560 nm in acetonitrile for quinhydrone and p-chloranil, respectively. The third method is based on the interaction of N-alkylvinylamine formed from the condensation of the free secondary amine group and acetaldehyde with p-chloranil to give a vinylamino substituted quinone. The coloured product exhibits an absorption maximum at 650 nm in dioxane. All variables were studied to optimize reaction conditions. Beer's law was obeyed and the relative standard deviations were found to be less than 1.5%. The methods have been applied to the analysis of nortriptyline hydrochloride in the bulk drug and in tablets.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine.

Cognitive dysfunction is common in older persons suffering from a major depression. However, the degree to which this dysfunction is reversible with successful treatment of the depression remains uncertain. The present study examined the effects that treatment (randomized double-blind design) with either an SSRI (paroxetine) or a tricyclic antidepressant (nortriptyline) had on cognition in older depressed patients. The patients' performance was compared to that of a group of normal controls of similar age and education. Patients and controls were administered measures of working memory, information-processing speed, episodic memory and attention five times over the course of a 12 week trial. At baseline, the patients performed more poorly than the elderly controls on all cognitive measures. While the patients' performance did improve over the course of their treatment, the magnitude of this improvement did not exceed that produced in the elderly controls by practice alone. The same pattern of results was evident in both intent-to-treat and responder analyses. Thus, there was no evidence that the depressed patients' cognitive performance normalized after response to antidepressant therapy. Neither the patients' age at onset nor their baseline level of cognitive functioning influenced the amount by which their performance improved over the 12 week trial. There was no difference between paroxetine and nortriptyline in the amount of cognitive change associated with treatment. The present results suggest that cognitive dysfunction persists in older depressed patients even after their mood disorder has responded to antidepressant medications.

Aged↗
PubMed2000

Determination of nortriptyline in human serum by fully automated solid-phase extraction and on-line high-performance liquid chromatography in the presence of antipsychotic drugs.

A fully automated on-line method for determination of nortriptyline in human serum was developed using an ASPEC XL (Gilson) solid-phase extraction apparatus in combination with high-performance liquid chromatography. Solid phase extraction was performed on cyanopropyl cartridges. HPLC was carried out using a C18 column with a mobile phase of acetonitrile-0.01 M triethylamine (34:66 v/v) buffer, pH 3.0. UV detection was at 242 nm. The Inter-day CV% was <5%. Comparison with liquid-liquid extraction of serum from patients treated with nortriptyline showed good agreement. Studies of analytical interference from coadministered psychoactive drugs revealed that only imipramine and a methotrimeprazine metabolite interfered.

Antidepressive Agents, Tricyclic↗
PubMed1979

Reliable routine method for the determination of plasma amitriptyline and nortriptyline by gas chromatography.

A gas chromatographic method has been developed for the determination of amitriptyline and nortriptyline in plasma. OV-17 is used in a 1 m long packed column, with a flame ionization detector and an electronic integrator. Five internal standards are added. The base-specific extraction procedure and the method of calibrating the chromatograph are described in detail. The accuracy, precision and reliability of the method are demonstrated by the results of nearly 700 determinations of each drug, at concentrations ranging from 5 to 400 ng/ml in the plasma. An interlaboratory comparison with a double radioactive isotope derivative assay for nortriptyline has also shown satisfactory agreement.

Amitriptyline↗
PubMed1996

Quantitative analysis of amitriptyline and nortriptyline in human plasma and liver microsomal preparations by high-performance liquid chromatography.

A simple, rapid, highly selective and sensitive method for the analysis of amitriptyline and nortriptyline in plasma and human liver microsomes is described. It is suitable for the routine analysis of large numbers of samples using readily available instrumentation and low cost consumables. The detection limit was 2 ng/ml for both compounds and calibration curves were linear over a wide range of concentrations and passed through the origin. The within-batch and between-batch coefficients of variation for amitriptyline and nortriptyline were less than 7.4% and 12.8%, respectively. A series of compounds, including inhibitors used for probing cytochrome P450 activity in vitro, were tested for interference in the assay. Only ketoconazole caused interference and the assay was modified to allow samples containing ketoconazole to be analysed.

Administration, Oral↗