Following the date of manufacture, amitriptyline hydrochloride preparations have expiration dates of 3-5 years depending on the manufacturer and dosage form.
分解：
When heated to decomposition it emits toxic fumes of /nitrogen oxides/
In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. The metabolism of this drug is subject to genetic polymorphisms. The main active metabolite is the secondary amine, _nortriptyline_. Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy. Other metabolites such as _cis-_ and _trans-10-hydroxyamitriptyline_ and _cis-_ and _trans-10-hydroxynortriptyline_ have the same pharmacologic profile as nortriptyline but are significantly weaker. _Demethylnortriptyline_ and amitriptyline N oxide are only present in plasma in negligible amounts; the latter is mostly inactive.
A method for the determination of amitriptyline and some of its metabolites in serum on a reversed phase system consisting of C-8 bonded phase material as the stationary phase and water-methanol-dichloromethane-propylamine as the mobile phase by liquid chromatography with UV detection at 254 nm is described. ... Serum levels of amitriptyline and its 4 main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxyamitriptyline and trans-10-hydroxynortriptyline) in a patient receiving 150 mg of oral amitriptyline daily are reported.
来源:Hazardous Substances Data Bank (HSDB)
代谢
阿米替林通过与其他三环类抗抑郁药相同的途径进行代谢；去甲替林，其N-单去甲基代谢物，具有药理活性。
Amitriptyline is metabolized via the same pathways as are other tricyclic antidepressants; nortriptyline, its N-monodemethylated metabolite, is pharmacologically active.
To investigate the metabolism of amitriptyline and debrisoquine ... 8 healthy Chinese volunteers received a single oral dose of 100 mg amitriptyline and the ratios between the area under the curve (AUC) of amitriptyline and its 3 metabolites were evaluated. Results indicated that large interindividual differences in AUC were observed. In addition, hydroxylation of amitriptyline and debrisoquine may be regulated by similar enzymatic processes.
Biotransformation of amitriptyline to its demethylated product nortriptyline was studied in vitro with human liver microsomes from four different donors, preselected to reflect a range of metabolic rates. Reaction velocity versus substrate concn was consistent with a sigmoid Vmax model. Vmax varied from 0.42 to 3.42 nmol/mg/min, Km from 33 to 89 uM amitriptyline. Ketoconazole was a highly potent inhibitor of N-demethylation, with a mean Ki value of 0.11 + or - 0.013 uM ... whereas quinidine (up to 50 uM), a CYP2D6 inhibitor, and alpha-naphthoflavone (up to 5 uM), a CYP1A2 inhibitor only at low concn, showed no effect. All selective serotonin reuptake inhibitors tested had an inhibitory effect on the formation of nortriptyline, with mean Ki values of 4.37 (+ or - 3.38) uM for sertraline, 5.46 (+ or - 1.95) uM for desmethylsertraline, 9.22 (+ or - 3.69) uM for fluvoxamine, 12.26 (+ or - 5.67) uM for norfluoxetine, 15.76 (+ or - 5.50) uM for paroxetine, and 43.55 (+ or - 18.28) uM for fluoxetine. A polyclonal rabbit antibody against rat liver CYP3A1, in antibody/microsomal protein rations varying from 1:1 to 10:1, inhibited N-demethylation of amitriptyline to an asymptotic max of 60%.
IDENTIFICATION AND USE: Amitriptyline is in the form of crystals. It is a tricyclic antidepressant. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose/poisoning may include the following: hypothermia, respiratory depression, seizures, abnormal tendon reflexes, disorientation, agitation, myoclonic jerks, coma, pyramidal signs, arrhythmias, bundle branch block, cardiac arrest, hypotension, circulatory collapse, mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decreased gastrointestinal motility, decreased bronchial secretions, and dry mucous membranes and skin. A study on children showed that initial symptoms and signs of acute amitriptyline intoxication appeared severe, but they disappeared with only supportive care required in most children except for cases that ingested high doses of drug within a few days. However, antidepressants have been shown to increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. An experiment with amitriptyline demonstrated that antidepressants reduce the release of non-neuronal acetylcholine in the human placenta, but only at concentrations roughly 30-fold above the therapeutic range. Antidepressant therapy of pregnant women should still be done with caution. Amitriptyline HCl was evaluated for its genotoxicity. The evaluation was performed in somatic (bone marrow) and germ (spermatocytes) cells, as well as the sperm morphology (i.e., head and tail) and count of the resulting sperm. The results showed that the treatment induced structural and numerical chromosome abnormalities in somatic cells (bone marrow) and germ cells (spermatocytes). Moreover, the drug significantly reduced both the mitotic index and meiotic activity after the different treatments used. Amitriptyline was found to increase significantly the incidence of sperm-cell head and tail abnormalities. The sperm-cell count was also significantly decreased. These results showed that the effect of the drug was dose dependent. In another study, amitriptyline was found to be nongenotoxic at plasma levels. However, frequencies of chromosome aberrations and sister chromatid exchanges were significantly increased at concentrations 4 and 40 times the plasma level. ANIMAL STUDIES: Symptoms of exposure in dogs include lethargy, tachycardia, vomiting, and hyperthermia. Symptoms in cats have included mydriasis and/or tachycardia, ataxia, lethargy, disorientation, and vomiting. In mice, amitriptyline produces rapid but reversible clouding of the lens, if the eyes are allowed to remain open and unprotected from evaporation. In a study on dogs, oral doses of 20 and 40 mg/kg/day were tolerated for 6 months without hematologic, biochemical or anatomical evidence of drug toxicity. Oral doses of 80 mg/kg/day were not well tolerated: 2 of 4 dogs died within 3 weeks after exhibiting severe ataxia and sedation. Doses of 100 mg/kg/day or greater were not tolerated for more than a few days. Offspring of amitriptyline-treated rats showed reduced locomotor activity. In rats, an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of cranial bones. Amitriptyline was tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. The drug was not genotoxic at concentrations up to 100 mM.
Amitriptyline is metabolized to nortriptyline which inhibits the reuptake of norepinephrine and serotonin almost equally. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.
Liver test abnormalities have been reported to occur in 10% to 12% of patients on amitriptyline, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported in patients on amitriptyline. The latency to onset is quite variable, ranging from 1 to 14 months of starting the medication. The reported pattern of serum enzyme elevations has varied from hepatocellular to cholestatic. An acute hepatitis-like syndrome with acute liver failure has been reported, as well as acute cholestatic hepatitis and prolonged jaundice compatible with vanishing bile duct syndrome. Signs or symptoms of hypersensitivity (rash, fever and eosinophilia) are frequent, but are usually mild and transient. Autoantibody formation is rare.
Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences.
Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination.
The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). It is found widely distributed throughout the body. Amitriptyline and the main metabolite _nortriptyline_ pass across the placental barrier and small amounts are present in breast milk.
The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h). No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased.
This study reports the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Five healthy Greyhound dogs were enrolled in a randomized crossover design. A single oral dose of amitriptyline hydrochloride (actual mean dose 8.1 per kg) was administered to fasted or fed dogs. Blood samples were collected at predetermined times from 0 to 24 hr after administration, and plasma drug concentrations were measured by liquid chromatography with mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Two dogs in the fasted group vomited following amitriptyline administration and were excluded from analysis. The range of amitriptyline CMAX for the remaining fasted dogs (n = 3) was 22.8-64.5 ng/mL compared to 30.6-127 ng/mL for the fed dogs (n = 5). The range of the amitriptyline AUCINF for the three fasted dogs was 167-720 hr ng/mL compared to 287-1146 hr ng/mL for fed dogs. The relative bioavailability of amitriptyline in fasted dogs compared to fed dogs was 69-91% (n = 3). The exposure of the active metabolite nortriptyline was correlated to amitriptyline exposure (R(2) = 0.84). Due to pharmacokinetic variability and the small number of dogs completing this study, further studies are needed assessing the impact of feeding on oral amitriptyline pharmacokinetics. Amitriptyline may be more likely to cause vomiting in fasted dogs.
AbstractA continuous flow protocol for the preparation of the tricyclic antidepressant (TCA) amitriptyline is reported. The advantages of flow chemistry when handling organometallic agents as well as when performing reaction with gases are demonstrated. Continuous multilithiation combined with carboxylation and the Parham cyclization, a Grignard addition and thermolytic water elimination by inductive heating are key features of the multistep protocol.magnified image
AbstractA continuous flow protocol for the preparation of the tricyclic antidepressant (TCA) amitriptyline is reported. The advantages of flow chemistry when handling organometallic agents as well as when performing reaction with gases are demonstrated. Continuous multilithiation combined with carboxylation and the Parham cyclization, a Grignard addition and thermolytic water elimination by inductive heating are key features of the multistep protocol.magnified image
A convenient new synthesis of quaternary ammonium glucuronides of drug molecules
摘要：
N-Glucuronides, of various Structural types, are frequently encountered as drug metabolites. Efficient chemical synthesis of these compounds, both as analytical standards and for toxicological investigation, is therefore an important goal. Earlier syntheses of N+-glucuronides of aliphatic tertiary amine drugs involved direct reaction of the drug molecule with a bromosugar, but yields were generally low and of poor reproducibility, with many by-products. In addition the final products were often of low stability, hindering effective isolation and purification. We now report that a stable, readily prepared glucuronic acid hemiacetal is a reliable precursor for metabolites of this type and give three pharmaceutically relevant examples. We report further on the stability of the final metabolites and the conditions required for their isolation and purification. (C) 2009 Elsevier Ltd. All rights reserved.
[EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
申请人：BIAL BIOTECH INVEST INC
公开号：WO2021055627A1
公开（公告）日：2021-03-25
The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
New Drug Delivery System for Crossing the Blood Brain Barrier
申请人：Lipshutz H. Bruce
公开号：US20070203080A1
公开（公告）日：2007-08-30
New ubiquinol analogs are disclosed, as well as methods of using these compounds to deliver drug moieties to the body.
新的泛醌类似物被披露，以及利用这些化合物将药物基团输送到人体的方法。
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
申请人：Dunn Robert
公开号：US20080318941A1
公开（公告）日：2008-12-25
The present disclosure provides compounds having affinity for the 5-HT
6
receptor which are of the formula (I):
wherein R
1
, R
2
, R
5
, R
6
, B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
