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PubMed2004

A case report of a poor metabolizer of CYP2D6 presented with unusual responses to nortriptyline medication.

We present a case with decreased metabolic activity of CYP2D6, a cytochrome P450 enzyme catalyzing the metabolism of nortriptyline (NT). Conventional dosage regimen led to toxic plasma concentration of NT and adverse effects such as dry mouth, constipation, and dizziness in this case with genotype CYP2D6*5/*10B. This case suggests the clinical usefulness of pharmacogenetic testing in individualized dosage adjustments of NT.

Antidepressive Agents, Tricyclic↗
PubMed1998

Determination of amitriptyline and nortriptyline in human liver microsomes with reversed-phase HPLC in vitro.

AIM: To develop a method for simultaneous determinations of amitriptyline (Ami) and its metabolite nortriptyline (Nor) in human liver microsomes. METHODS: An incubation buffer containing microsomes, NADPH-generating system, and Ami, after termination of enzyme reaction and desipramine (Des) as internal standard (IS), was extracted with diethy ether and separated on a reversed-phase ODS column. Detection was achieved at 242 nm by ultraviolet detector. RESULTS: No potential interfering peaks were found. Ami and Nor gave rapid elution and baseline resolution. The linear curves of both analyses ranged 0.02-10 nmol and the limit of detection was 0.01 nmol. The recovery (94%-101%) had good precision with relative s of < 8.3%. CONCLUSION: This method is rapid, sensitive, and simple for studying the metabolism of Ami and Nor.

Amitriptyline↗
PubMed1999

Extrapyramidal symptoms associated with the adjunct of nortriptyline to a venlafaxine-valproic acid combination.

The onset of extrapyramidal symptoms has been traditionally linked to the prescription of neuroleptic treatment: there are some reports in the international literature describing extrapyramidal effects related to antidepressant. In this paper we present a case under multiple pharmacologic treatment in whom extrapyramidal symptoms developed shortly after the adjunct of nortriptyline to a combination of venlafaxine and valproic acid administered for several months. We describe here the clinical history of this patient, affected by Bipolar Disorder, type II, and the progressive pharmacologic path in his treatment. Possible hypothesis to explain this evidence are discussed.

Aged↗
PubMedDate not supplied

Effects of nortriptyline and paroxetine on postural sway in depressed elderly patients.

Tricyclic antidepressants (TCAs) have previously been found to be related to an increased incidence of falls in elderly persons. Recent pharmacoepidemiologic and nursing home studies have suggested that the risk of falls and fractures in elderly patients receiving selective serotonin reuptake inhibitors (SSRIs) is not different from that of patients receiving TCAs. The authors therefore evaluated postural sway in an older population of depressed patients randomly assigned to treatment with either nortriptyline or paroxetine and did not find any change in postural sway after 6 weeks' treatment with either antidepressant. Further studies with other SSRIs are needed.

Aged↗
PubMed1992

On-line solid-phase extraction and high-performance liquid chromatographic determination of nortriptyline and amitriptyline in serum.

An isocratic reversed-phase high-performance liquid chromatographic method with on-line solid-phase extraction for the simultaneous determination of amitriptyline and nortriptyline in serum has been developed. A 250-microliters serum sample is injected directly onto a commercially available CN cartridge and, after a washing step, the retained solutes are backflushed onto a bonded-phase CN column using a column-switching technique and a mobile phase composed of acetonitrile (26%) and 0.05 M phosphate buffer with diethylamine. Serum is diluted with 0.1 M sodium lauryl sulphate and centrifuged before the injection. Detection at 210 nm ensures sufficient sensitivity. The recovery is almost quantitative and the relative standard deviation ranges from 2.8 to 8.0% for concentrations of 200-40 ng/ml. Being rapid and simple, the method is convenient for routine use.

Amitriptyline↗
PubMed1992

Metabolite intermediate complexation of microsomal cytochrome P450 2C11 in male rat liver by nortriptyline.

Antidepressant drugs that contain alkylaminoalkyl substituents have been associated with serious pharmacokinetic interactions in humans that may be related to the inhibition of cytochrome P450 (P450) enzymes. In this study, the propensity of the tricyclic antidepressant nortriptyline (NOR) to inhibit individual microsomal P450 enzymes in rat liver was investigated to provide a mechanistic explanation for these pharmacokinetic interactions. Enzyme kinetic studies revealed that NOR inhibited steroid 2 alpha-, 6 beta, 7 alpha-, and 16 alpha-hydroxylation in untreated rat liver with Km/Ki ratios of 0.53, 0.59, 0.25, and 0.29, respectively. When the drug was preincubated with microsomes and NADPH before testosterone hydroxylation was conducted, marked increases in the Km/Ki ratios were observed (to 8.8, 3.9, 0.62, and 13, respectively). Thus, enzymic oxidation of NOR enhanced its inhibition capacity against P450 activities. Indeed, the altered Km/Ki ratios indicate 17-, 6.6-, 2.5-, and 47-fold increases in inhibition of the four pathways of testosterone hydroxylation after the biotransformation of NOR to its metabolites. From these experiments it was apparent that testosterone 2 alpha- and 16 alpha-hydroxylations, catalyzed predominantly by P450 2C11, were subject to the most pronounced increase in inhibition. Under these conditions, the apparent content of microsomal P450 was decreased, thus suggesting the formation of a NOR metabolite intermediate (MI) complex with the cytochrome. Further, optical difference spectroscopy of NADPH-supported metabolism of NOR in microsomes and in a reconstituted system incorporating purified P450 2C11 indicated the appearance of an absorbance peak near 454 nm, similar to those produced by triacetyloleandomycin, SKF 525-A, and orphenadrine. Formation of this absorbance peak in microsomes was inhibited by an antibody raised against the male-specific P450 2C11. Because oxidative metabolism of NOR to inhibitory products would not necessarily involve MI complexation, additional experiments were undertaken in which NOR-related free metabolites produced in microsomal incubations were removed on Sep-Pak mini-C18 columns before estimation of testosterone hydroxylation. The principal finding from this experiment was that P450 3A2-dependent steroid 6 beta-hydroxylase activity was inhibited to a much lesser extent after removal of unbound NOR metabolites on Sep-Pak columns (25% inhibition after Sep-Pak extraction, compared with 82% inhibition observed when all NOR metabolites were present during subsequent testosterone hydroxylation); inhibition of P450 2C11-mediated 2 alpha- and 16 alpha-hydroxylation was not noticeably different after Sep-Pak treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Comparative cardiotoxicity of nortriptyline and its isomeric 10-hydroxymetabolites.

The potential cardiotoxicity of the hydroxymetabolites of nortriptyline (NT) has been raised by inferential data from clinical studies and by the experimentally demonstrated cardiac effects of 2-OH-imipramine. Cardiac output, arterial pressure, and a continuous electrocardiogram were assessed after intravenous de novo administration of NT or its hydroxymetabolites to 41 swine. NT at doses ranging from 3.5 to 7 mg base per kilogram caused significantly more arrhythmias than did E-10-hydroxynortriptyline (E-10-OH-NT) but was not significantly different from Z-10-hydroxynortriptyline (Z-10-OH-NT) in this effect. Z-10-OH-NT, in contrast, to its geometrical isomer caused marked bradycardia, and decrements in blood pressure and cardiac output. NT and Z-10-OH-NT, but not E-10-OH-NT, produced dose-correlated declines in cardiac output. The hydroxymetabolites had smaller volumes of distribution, shorter half-lives and larger free fractions compared with NT. The differing cardiotoxicity of the hydroxymetabolites could not be accounted for by differing pharmacokinetic properties.

Animals↗
PubMed1991

Verbal memory and plasma drug concentrations in elderly depressives treated with nortriptyline.

Performance on a verbal memory task and affective state were assessed in geriatric major depressives before and during 6 weeks of treatment with nortriptyline (NT) in a fixed-dose design study. Higher plasma NT concentration was associated with poorer free recall but better affective outcome. In contrast, higher plasma Z-10-hydroxynortriptyline (Z-10-OH-NT) concentration was associated with more efficient free recall. Concentration-effect relationships were noted in patients later classified as cognitively unimpaired using the Dementia Rating Scale after optimal treatment, rather than in those with residual cognitive impairment.

Aged↗
PubMed1991

Effects of alpha-1-acid glycoprotein on the cardiovascular toxicity of nortriptyline in a swine model.

Tricyclic antidepressant toxicity is a frequently encountered and life-threatening problem in emergency medicine. This trial investigated the effect of alpha-1-acid glycoprotein (AAG), an acute phase reactant with a high affinity for basic drugs, on the clinical and pharmacological manifestations of nortriptyline (NT) toxicity. Fourteen pentobarbital-anesthetized swine (10-13 kg) were given a 10-min loading dose followed by a 45-min maintenance infusion of NT to achieve a plasma level of approximately 1000 ng/ml. At the end of the infusion, 7 control (C) animals were given 50 ml of 0.9% saline and 7 AAG animals were given 50 ml of 10% AAG, both over 15 min. Heart rate, QRS duration, QTc interval, blood pressure, temperature, arterial blood gases, albumin, and plasma-free and plasma-bound NT levels were measured at baseline and at every hour for 4 h. One death was noted in the AAG group and none in the C group (p = NS). Mean total NT levels after infusion in the C group was 1240 +/- 1118 ng/ml and in the AAG group 804 +/- 194 ng/ml (p = NS). No significant differences were found in the plasma-free fractions between groups at any time interval. However, significantly shorter QTc intervals were found during treatment with AAG compared to controls (P = 0.02). A trend toward increased systolic blood pressure (p = 0.09) and shorter QRS duration (p = 0.09) was noted during AAG treatment. No significant changes were shown between groups with respect to heart rate, arterial blood gases, or albumin measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The influence of ethanol on the distribution of amitriptyline and nortriptyline in rats.

The influence of ethanol in single and multiple doses on concentration-time profile of amitriptyline (1) and nortriptyline (2) in rat serum, brain, heart, and liver was studied. AUC0-6 values were calculated and statistically compared as well as cmax values in serum and tissues. Ethanol inhibited N-demethylation of 1 and therefore 2 has not been detected in biological material. AUC0-6 and cmax values were less than in control group. All AUC0-6 and cmax values for 1 in ethanol treated groups of rats were statistically significant compared with the control group.

Amitriptyline↗
PubMed1990

Double-blind placebo-controlled study of nortriptyline in depressed adolescents using a "fixed plasma level" design.

We performed a random assignment, double-blind, placebo-controlled study of nortriptyline (NT) in postpubertal 12- to 17-year-olds with Research Diagnostic Criteria (RDC) and DSM-III major depressive disorder. The protocol included a 2-week placebo washout phase and an 8-week double-blind, placebo-controlled phase with weekly plasma level monitoring. Active subjects had their plasma level placed at 80 +/- 20 ng/ml by using previously developed tables to determine the starting dose from a plasma level drawn 24 hours after a single dose administered at baseline. The study population was severely depressed and had a chronic, unremitting course prior to study; a high percentage of family histories with affective disorder, alcoholism, and suicidality; and a high rate of comorbidity. Of the 52 subjects enrolled, there were 17 placebo washout responders, 4 dropouts, and 31 completers (12 active and 19 placebo). Only one active subject responded; therefore, the study was terminated early. The mean NT plasma level was 91.1 (18.3 SD) ng/ml. The two treatment groups had similar postprotocol severity ratings. Subjects on active drug did not evidence the anticholinergic side effects reported in adult samples. The negative outcome in this study is similar to the findings in our previously reported NT study in prepubertal 6- to 12-year-olds.

Adolescent↗
PubMed1990

The effect of nortriptyline in elderly patients with cardiac conduction disease.

Ten depressed, elderly patients with cardiac conduction abnormalities were given therapeutic doses of nortriptyline. Serial ECGs revealed no clinically significant adverse cardiac changes. These data, added to the findings of previous research, suggest that tricyclic antidepressants (TCAs) present little risk in patients with first degree atrioventricular block or hemiblock. Patients with bundle-branch block and bifascicular block are at greater risk of adverse cardiac sequelae but can be treated with TCAs. To maximize safety, the authors recommend monitoring serial ECGs and plasma TCA levels.

Aged↗
PubMed1989

Treatment of premenstrual depression with nortriptyline: a pilot study.

There are no reports on treatment of premenstrual syndrome with antidepressants, although depression is a common symptom of the syndrome. Eleven women who met DSM-III-R criteria for late luteal phase dysphoric disorder were treated with nortriptyline in an open pilot study after they failed to respond to placebo or another medication. Eight of 11 patients had a good therapeutic response. The efficacy of antidepressants in the treatment of premenstrual depression needs confirmation with double-blind studies.

Adult↗
PubMedDate not supplied

Phenolic metabolites of amitriptyline and nortriptyline in rat bile.

Anesthetized bile fistula rats received amitriptyline (AT), its N-oxide (AT-NO), or nortriptyline (NT) at doses of 72 mumol/kg ip, and bile was collected for 6-9 hr. Isolation of metabolites was achieved by enzymic deconjugation and repeated TLC of extracted aglycones. Purified compounds were characterized by UV, NMR, and mass spectrometry, by color reactions, and by chemical interconversions. Besides the alcohols E-10-hydroxy-AT and 10,11-dihydroxy-AT, the phenol E-2-hydroxy-AT occurred as a major AT metabolite, while 2,10- and 2,11-dihydroxy-AT, 2,10,11-trihydroxy-AT, and 2-hydroxy-3-methoxy (or 3-hydroxy-2-methoxy)-AT were present in smaller quantities. Further minor metabolites were 2-hydroxy-11-oxo-AT, 3-hydroxy-AT, 3,11-dihydroxy-AT, and its dehydration product 3-hydroxy-10,11-dehydro-AT. The exact position of the functional groups was elucidated by the nuclear Overhauser effect (NOE) in NMR spectroscopy and by analyzing metabolite patterns in the bile of rats given E- or Z-10-hydroxy-AT. Administration of AT-NO led to a larger proportion of methylated catechols and a smaller one of 10-hydroxy metabolites. Besides the tertiary amines, rats given AT or AT-NO excreted the demethylated analogues of some of the hydroxylation products. The latter also occurred as metabolites of NT, the ratio of aromatic and aliphatic hydroxylation being lower than with AT or AT-NO. Urine of rabbits treated orally with AT contained mono- and dihydroxylated metabolites resulting from attack at positions 2, 3, 10, and/or 11 and the same methylated catechols as rat bile.

Amitriptyline↗
PubMedDate not supplied

Glucuronides of hydroxylated metabolites of amitriptyline and nortriptyline isolated from rat bile.

Polar conjugates were isolated from the bile of rats given amitriptyline (AT, unlabeled or labeled with 14C), nortriptyline (NT), or 10-hydroxy (10-OH) derivatives of the drugs. The procedure involved extraction on a column of polystyrene resin, elution with methanol, and separation by preparative TLC followed by reversed phase HPLC. Individual metabolites were characterized by NMR spectroscopy and fast atom bombardment mass spectrometry and by enzymatic or acid deconjugation with subsequent identification of aglycones and glucuronic acid. Conversely, they were compared with conjugates obtained from hydroxy compounds by incubation with rat liver microsomes and UDP-glucuronic acid. Glucuronides isolated from the bile of rats given AT were derived from 2-OH-AT, (E)- and (Z)-10-OH-AT, 2-hydroxy-3-methoxy- (or 3-hydroxy-2-methoxy) AT, 10, 11-(OH)2-AT, and some of the N-demethylated analogues of these compounds. In most cases, 10-OH compounds form two diastereoisomeric glucuronides produced from the enantiomeric alcohols; 10, 11-(OH)2 metabolites occur as cis- and trans-isomers that are conjugated with glucuronic acid. Administration of synthetic (E)- and (Z)-10-OH-AT and -NT leads to the excretion of their glucuronides along with conjugates formed after demethylation and/or introduction of a second OH group. NT gives rise to 2-OH-NT glucuronide besides those conjugates derived from (E)-10-OH-NT. No glutathione conjugates could be detected.

Amitriptyline↗
PubMed1987

Effects of nortriptyline and its 10-hydroxy metabolite on plasma noradrenaline (NA) concentrations, heart rate and blood pressure during intravenous NA infusion.

Eight healthy subjects were randomly given placebo and equimolar doses of nortriptyline (NT) and E-10-hydroxy-NT (E-10-OH-NT). Two hours after oral intake of drug, noradrenaline (NA) was infused intravenously at three consecutive rates. Before infusion of NA, E-10-OH-NT significantly increased heart rate compared to NT (p less than 0.05) and placebo (p less than 0.01). During NA infusion, the active drugs caused non-significant tendencies to augmented increase of blood pressure and decrease of heart rate. Plasma NA concentrations increased significantly due to the infused NA but were not influenced by NT or E-10-OH-NT. This absence of drug effect may have been due to several simultaneously operating factors affecting plasma NA concentrations, e.g., modification of the rates of NA release and clearance by exogenous NA or drugs and competing elimination pathways for infused NA. After stopping the NA infusion, a non-significant tendency to a slower elimination of NA was found after both active drugs.

Adult↗