Res Commun Chem Pathol Pharmacol. 1978 Dec;22(3):475-84.
The kinetics of amitriptyline following single oral dose administration to man.

Garland WA, Min BH, Birkett DJ.

Amitriptyline and its metabolite, nortriptyline, were measured in the plasma of eight humans for 96 hours following oral administration of a 75 mg dose of amitriptyline hydrochloride. Based on the 8 to 96 hour post dosing plasma concentration data, the terminal exponential half life of amitriptyline +/- S.D. was 22.4 +/- 4.3 hr. Based on the 24 to 96 hour concentration data, the "apparent" terminal half time of nortriptyline +/- S.D. was 26.0 +/- 7.4 hours for seven subjects. For these same seven subjects the relative area under the plasma concentration time curve of nortriptyline +/- S.D. was only 0.88 +/- 0.34 times that of amitriptyline. One subject whose apparent nortriptyline half time was 108 hours had a nortriptyline bioavailability 3.83 times that of amitriptyline. Average steady state plasma levels for 12 psychiatric patients who had received a 50 mg oral dose of amitriptyline three times a day for an average of 32 days could be predicted from the single dose plasma clearance of amitriptyline.

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cyf-kr.edu.pl

The aim of this study was to search for possible effects of imipramine and amitriptyline on the pharmacokinetics and metabolism of perazine at steady state in rats. Perazine (10 mg kg(-1), i.p.) was administered to rats twice daily for two weeks, alone or jointly with imipramine or amitriptyline (10 mg kg(-1) i.p.). Concentrations of perazine and its two main metabolites (5-sulphoxide and N-desmethylperazine) in the plasma and brain were measured at 30 min (Cmax), 6h and 12h (slow disposition phase) after the last dose of the drugs. Liver microsomes were prepared 24 h after withdrawal of the drugs. Amitriptyline increased the plasma and brain concentrations of perazine (up to 300% of the control) and N-desmethylperazine, while not affecting those of 5-sulphoxide. Imipramine only tended to increase the neuroleptic concentration in the plasma and brain. Studies with control liver microsomes showed that amitriptyline and imipramine added to the incubation mixture in-vitro, competitively inhibited N-demethylation (Ki (inhibition constant) = 16 microM and 164 microM, respectively) and 5-sulphoxidation (Ki = 57 microM and 86 microM, respectively) of perazine, amitriptyline being a more potent inhibitor of perazine metabolism, especially with respect to N-demethylation. Studies with microsomes of rats treated chronically with perazine or tricyclic antidepressants, or both, did not show significant differences in the rate of perazine metabolism between perazine- and perazine+antidepressant-treated rats. The data obtained were compared with the results of analogous experiments with promazine and thioridazine. It was concluded that elevations of perazine concentration were caused by direct inhibition of the neuroleptic metabolism by the antidepressants. Similar interactions, possibly leading to exacerbation of the pharmacological action of perazine, may be expected in man. Since the interactions between phenothiazines and tricyclic antidepressants may proceed in two directions, reduced doses of both the neuroleptic and the antidepressant are recommended when the drugs are administered jointly.

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zeus.bwh.harvard.edu

BACKGROUND: Amitriptyline, a tricyclic antidepressant, is frequently used orally for the management of chronic pain. To date there is no report of amitriptyline producing peripheral nerve blockade. The authors therefore investigated the local anesthetic properties of amitriptyline in rats and in vitro. METHODS: Sciatic nerve blockade was performed with 0.2 ml amitriptyline or bupivacaine at selected concentrations, and the motor, proprioceptive, and nociceptive blockade was evaluated. Cultured rat GH3 cells were externally perfused with amitriptyline or bupivacaine, and the drug affinity toward inactivated and resting Na+ channels was assessed under whole-cell voltage clamp conditions. In addition, use-dependent blockade of these drugs at 5 Hz was evaluated. RESULTS: Complete sciatic nerve blockade for nociception was obtained with amitriptyline for 217 +/- 19 min (5 mM, n = 8, mean +/- SEM) and for 454 +/- 38 min (10 mM, n = 7) versus bupivacaine for 90 +/- 13 min (15.4 mM, n = 6). The time to full recovery of nociception for amitriptyline was 353 +/- 12 min (5 mM) and 656 +/- 27 min (10 mM) versus 155 +/- 9 min for bupivacaine (15.4 mM). Amitriptyline was approximately 4.7-10.6 times more potent than bupivacaine in binding to the resting channels (50% inhibitory concentration [IC50] of 39.8 +/- 2.7 vs. 189.6 +/- 22.3 microM) at - 150 mV, and to the inactivated Na+ channels (IC50 of 0.9 +/- 0.1 vs. 9.6 +/- 0.9 microM) at -60 mV. High-frequency stimulation at 3 microM caused an additional approximately 14% blockade for bupivacaine, but approximately 50% for amitriptyline. CONCLUSION: Amitriptyline is a more potent blocker of neuronal Na+ channels than bupivacaine in vivo and in vitro. These findings suggest that amitriptyline could extend its clinical usefulness for peripheral nerve blockade.

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kure-nh.go.jp

Modulation of neurotrophic factors to protect neurons from damage is proposed as a novel mechanism for the action of antidepressants. However, the effect of antidepressants on modulation of glial cell line-derived neurotrophic factor (GDNF), which has potent and widespread effects, remains unknown. Here, we demonstrated that long-term use of antidepressant treatment significantly increased GDNF mRNA expression and GDNF release in time- and concentration-dependent manners in rat C6 glioblastoma cells. Amitriptyline treatment also increased GDNF mRNA expression in rat astrocytes. GDNF release continued for 24 h following withdrawal of amitriptyline. Furthermore, following treatment with antidepressants belonging to several different classes (amitriptyline, clomipramine, mianserin, fluoxetine and paroxetine) significantly increased GDNF release, but which did not occur after treatment with non-antidepressant psychotropic drugs (haloperidol, diazepam and diphenhydramine). Amitriptyline-induced GDNF release was inhibited by U0126 (10 microM), a mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89 (1 microM), a protein kinase A inhibitor, calphostin C (100 nM), a protein kinase C inhibitor and PD 169316 (10 microM), a p38 mitogen-activated protein kinase inhibitor. These results suggested that amitriptyline-induced GDNF synthesis and release occurred at the transcriptional level, and may be regulated by MEK/MAPK signalling. The enhanced and prolonged induction of GDNF by antidepressants could promote neuronal survival, and protect neurons from the damaging effects of stress. This may contribute to explain therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.

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Eur J Pharmacol. 2001 Nov 2;430(2-3):211-8.
Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: multiple interactions.

Esser MJ, Chase T, Allen GV, Sawynok J.

Departments of Pharmacology and Anatomy and Neurobiology, Dalhousie University, Nova Scotia, B3H 4H7, Halifax, Canada.

This study was designed to determine (1) whether chronic amitriptyline administration was effective in alleviating symptoms of neuropathic pain in a rat model of spinal nerve injury, and (2) whether the effect of amitriptyline involved manipulation of endogenous adenosine, by determining the effect of caffeine, a non-selective adenosine A(1) and A(2) receptor antagonist, on its actions. Nerve injury was produced by unilateral spinal nerve ligation of the fifth and sixth lumbar nerves distal to the dorsal root ganglion, and this resulted in stimulus-evoked thermal hyperalgesia and static tactile mechanical allodynia. Animals received pre- and post-surgical intraperitoneal doses of amitriptyline (10 mg/kg) and caffeine (7.5 mg/kg), alone or in combination, and following surgery, were administered amitriptyline (15-18 mg/kg/day) and caffeine (6-8 mg/kg/day), alone or in combination, in the drinking water. Rats were tested for thermal reaction latencies and static tactile thresholds at 7, 14 and 21 days following surgery. In the paw ipsilateral to the nerve ligation, chronic amitriptyline administration consistently decreased the thermal hyperalgesia produced by spinal nerve ligation over a 3-week period, and this effect was blocked by concomitant caffeine administration at all time intervals. In the contralateral paw, thermal withdrawal latencies were more variable, with the most reproducible finding being a reduction in thermal thresholds in the amitriptyline-caffeine combination group. There was no effect by either drug or the drug combination on the static tactile allodynia produced by spinal nerve ligation in the ipsilateral paw. However, chronic amitriptyline administration induced a tactile hyperaesthesia in the contralateral paw at all time intervals, and this effect was exacerbated by concomitant chronic caffeine administration. The results of this study indicate that chronic administration of amitriptyline is effective in alleviating thermal hyperalgesia, but not static tactile allodynia, in the hindpaw ipsilateral to nerve injury, and the block of this effect by caffeine suggests that this effect is partially achieved through manipulation of endogenous adenosine systems. Additionally, chronic amitriptyline administration induces contralateral hyperaesthetic responses that are augmented by caffeine. Both the symptom-specific effect, and adenosine involvement in amitriptyline action may be important considerations governing its use in neuropathic pain.

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eu.pnu.com

The polarity and viscosity of the microenvironment of aggregates of the cationic amphiphilic drug amitriptyline and dextran sulfate (DxS)/carrageenan-amitriptyline aggregates in aqueous solution were investigated by means of steady state and time-resolved fluorescence. For the latter systems, equilibrium dialysis and capillary viscometry were also used. The micropolarity as detected by pyrene indicated the formation of amitriptyline aggregates, both with and without polyelectrolyte, having properties similar to "traditional" cationic micelles. The pyrene lifetime in the amitriptyline- and amitriptyline-polyelectrolyte aggregates was long ( approximately 230 and approximately 300 ns, respectively), indicating that pyrene was well protected from oxygen quenching, especially so in the latter case. The microviscosity of the amitriptyline aggregates themselves, and in the presence of polyelectrolyte, was high, as indicated by intramolecular excimer formation of 1,3-di(1-pyrenyl)-propane (P3P), rotational diffusion fluorescence depolarization of 1,6-diphenyl-1,3,5-hexatriene (DPH), and intramolecular rotational relaxation about bonds of [p-(dimethylamino)benzylidene]-malonitrile (BMN). These results and the concurrent decrease of the bulk viscosity indicate that the polyelectrolyte, acting as polycounterion, is tightly wrapped around the amitriptyline aggregates. Amitriptyline hence behaves in accordance with accepted models of cationic surfactant-polyelectrolyte interaction. Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1665-1677, 2001

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Toxicol Appl Pharmacol. 2001 Dec 15;177(3):179-87.
A study of mechanisms underlying amitriptyline-induced acute lung function impairment.

Svens K, Ryrfeldt A.

Division of Inhalation Toxicology, Karolinska Institutet, Stockholm, S-171 77, Sweden.

In this study possible mechanisms underlying the vaso- and bronchoconstriction caused by the tricyclic antidepressant drug amitriptyline in isolated rat lungs were investigated. Some features here are similar to those apparent in adult respiratory distress syndrome and acute lung injury. Amitriptyline exposure (50 and 100 microM) caused a dose-related, pronounced, and rapid vaso- (50 microM, 30 min, p < 0.001 and 100 microM, 30 min, p < 0.001) and bronchoconstriction (50 microM, 30 min, p = 0.01 and 100 microM, 30 min, p < 0.001). The maximal noted decrease in perfusion flow was 28 +/- 2.9% at 25 min and 80 +/- 4.5% at 30 min for 50 and 100 microM amitriptyline, respectively. The maximal noted decrease in airway conductance was 29 +/- 4.7% at 25 min and 68 +/- 5.0% at 30 min. To investigate mechanisms thought to be involved in amitriptyline-induced lung function impairment, lungs were treated with several different substances including antiinflammatory agents, antioxidants, inhibitors of enzymes involved in the arachidonic acid cascade, physiological antagonists, and neurogenic antagonists. A significant reduction of amitriptyline-induced vasoconstriction was observed when lungs were treated with the protein kinase inhibitor staurosporine (3 microM, 30 min, p < 0.001), the NO-donor S-nitrosoglutathione (100 microM, 30 min, p < 0.001) and the combined endothelin A/endothelin B receptor antagonist PD 145065. This latter inhibitor caused a significant attenuation of late vasoconstriction (1 microM, 60 min, p = 0.03). The amitriptyline-induced bronchoconstriction was attenuated by the beta(2)-agonist salbutamol (1 microM, 30 min, p = 0.03) and the platelet-activating factor antagonist WEB2086 (10 microM, 30 min, p = 0.03). Staurosporine had an initial protective effect on bronchoconstriction (3 microM, 5 min, p = 0.003), while PD145065 significantly decreased bronchoconstriction 60 min after start of amitriptyline exposure (1 microM, 30 min, p = 0.003). This indicates that endothelin as well as platelet activating factor and protein kinase activation are important in mediating amitriptyline-induced lung function impairment in our experimental model and perhaps also in acute lung injury. c)2001 Elsevier Science.

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