Arch Androl. 1984;12(1):25-8.
Sperm immobilizing potency of amitriptyline and imipramine: measured with transmembrane migration.

Hong CY, Chiang BN, Ku J.

The inhibitory effect of amitriptyline and imipramine on human sperm motility was measured in vitro with a transmembrane migration method. The EC50 for amitriptyline and imipramine were 170 microM and 160 microM respectively. They were more potent than any other drug that had been tested on this pharmacological model. Transmembrane migration method was less sensitive than turbidimetric method to detect the sperm immobilizing effect of drugs.

PIP: The sperm immobilizing effect of 2 frequently prescribed antidepressants--amitriptyline and imipramine--was measured with a transmembrane migration method. Results were compared with those obtained by torbidimetric method. In addition, the potencies of these 2 drugs were compared with other sperm immobilizing agents, so the underlying mechanism and clinical implication could be elucidated. Fresh human semen samples were collected from healthy donors. Drug treated sperm motility was calculated from the proportion of sperm that moved across the membrance from semen drug mixture into phosphate buffered saline during 2 hour incubation at 37 degrees Centigrade. The motility of sperm in semen mexed with phosphate buffered saline was used as control. The drug treated sperm motility was expressed as percentage of control and plotted on a semilog paper. The concentration of drug that decreased sperm motility of 50% of control (EC50) was obtained from the concentration response curve. The EC50 for amitriptyline and imipramine were 170 mcgM and 160 mcgM, respectively. The difference between these 2 drugs at all concentrations was not significant. The clinical implication for determing the sperm immobilizing potency of drugs in vitro is uncertain at this time. The EC50 is nearly a hundred times higher than the therapeutic blood levels of these drugs. In addition, such an in vitro test investigates the acute effect of drugs only; longterm effect, as well as the effect of the metabolites, were not included. The potential value of developing sperm motility as a cellular model for pharmacological research is confirmed in this study.

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J Pharm Sci. 1977 Jan;66(1):77-81.
Quantitative determination of amitriptyline and its principal metabolite, nortriptyline, by GLC-chemical ionization mass spectrometry.

Garland WA.

A quantitative GLC-mass spectrometry assay was developed for the determination of the tricyclic antidepressant amitriptyline and its desmethyl metabolite (nortriptyline) in human plasma. The assay utilizes selective ion detection to monitor in a GLC effluent the MH+ molecular ions of amitriptyline and nortriptyline generated by isobutane chemical ionization. The procedure, which utilizes deuterated analogs of amitriptyline and nortriptyline as internal standards, requires 1 ml of plasma and can measure 1 ng/ml of amitriptyline and 0.5 ng/ml of nortriptyline. The curves relating the amounts of amitriptyline and nortriptyline added versus the amounts found over a 100-fold range of amitriptyline and nortriptyline concentrations are straight lines with intercepts of approximately zero and slopes of unity. Analyses of plasma samples from three subjects receiving 50 mg of amitriptyline orally, three times a day, gave an average plasma concentration of 115 +/- 42 ng/ml for amitriptyline and 109 +/- 20 ng/ml for nortriptyline. Similar analyses of the plasma of three subjects who had received a single 50-mg oral dose of amitriptyline showed an average maximum plasma concentration of 25 +/- 10 ng/ml for amitriptyline and 10 +/- 4 ng/ml for nortriptyline. Seventy-two hours after adminis-ration, the average plasma amitriptyline and nortriptyline levels were 3 +/- 2 ng/ml, respectively.

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Neuropsychobiology. 1989;20(3):132-5.
Acute amitriptyline effects on parasympathetic-evoked rat saliva.

Yu JH, Chen YY, Suarez K.

Georgetown University School of Dentistry, Washington, D.C.

The present study was undertaken to investigate the acute effects of amitriptyline on salivary secretion evoked by electrical stimulation of the parasympathetic innervations of rat salivary glands. Single intravenous injections of amitriptyline (0.1-1 mg/kg) caused a dose-related decrease in flow and Na concentration of saliva from both parotid and submandibular glands. However, the only effect on K concentration was a slight increase when the salivary flow was almost completely inhibited. Amitriptyline increased the Ca concentration of nerve-evoked submandibular saliva, but had no effect on the Ca concentration of similarly evoked parotid saliva. However, amitriptyline (0.5 and 1 mg/kg) increased the protein concentration of both kinds of saliva. Amylase activity of parotid saliva was also moderately increased by amitriptyline. These effects were similar to those observed with atropine, a known cholinergic receptor antagonist. These results suggest that amitriptyline, like atropine, reduces parasympathetic-evoked salivary secretion by blocking cholinergic receptors.

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Circulation. 1985 Oct;72(4):898-906.
Frequency-dependent effects of amitriptyline on ventricular conduction and cardiac rhythm in dogs.

Nattel S.

Although overdoses of tricyclic antidepressant are known to produce both sinus tachycardia and ventricular tachyarrhythmias in man, these have been assumed to occur by independent mechanisms. This study was designed to evaluate the relationship of ventricular activation frequency to the cardiotoxic effects of amitriptyline. When amitriptyline was infused into dogs with formalin-induced atrioventricular (AV) block to evaluate a broad range of pacing frequencies, the drug produced dose-related QRS prolongation that was markedly frequency dependent. Similar frequency-dependent depression of the maximum rate of depolarization (Vmax) was noted for canine Purkinje fibers superfused with amitriptyline in vitro. The time constant of recovery from amitriptyline-induced block was dose independent and averaged 228 msec in vivo and 216 msec in vitro. When amitriptyline was infused into dogs with intact AV conduction, sinus tachycardia occurred within 15 min, followed by progressive QRS prolongation and ventricular tachyarrhythmias after an average 29 min. Slowing of sinus rate by vagal stimulation (seven dogs) or intravenous metoprolol (five dogs) reproducibly reversed the QRS prolongation and ventricular tachyarrhythmias caused by amitriptyline. These studies show that amitriptyline produces frequency-related depression of ventricular conduction in vivo, with a time dependence similar to effects on the maximum rate of depolarization in vitro. Interventions that slow heart rate reverse the adverse effects of amitriptyline on ventricular conduction and cardiac rhythm.

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Eur J Clin Pharmacol. 1977 Nov 14;12(3):187-90.
Comparative bioavailability of a sustained release preparation of amitriptyline and conventional tablets.

Jorgensen A.

A sustained release preparation of amitriptyline has been compared with conventional tablets in eight healthy human volunteers. The tablet produced a distinct peak in serum concentration shortly after administration, whereas the sustained release preparation caused a slow rise to a plateau. The maximum serum concentration and the time of its occurrence differed significantly between the two preparations. The differences between the serum concentration curves of the two preparations can be explained on the basis of a two compartment model of amitriptyline pharmacokinetics and from a difference in the absorption rate. The similar clinical effect obtained with a lower daily dose of the sustained release preparation than of the tablet cannot be accounted for in terms of pharmacokinetics. It is possible that a single evening dose of sustained release amitriptyline gives a more appropriate serum concentration profile of amitriptyline and its active metabolite nortriptyline than a conventional tablet taken three times a day.

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Br J Pharmacol. 1978 Jun;63(2):315-21.
The effect of amitriptyline on presynaptic mechanisms in noradrenergic nerves.

Hughes IE.

1 Electrically evoked and resting overflow of tritium was measured from mouse vas deferens previously incubated with [3H]-(--)-noradrenaline. 2 At low concentrations (1.6 X 10(-7) to 4 X 10(-6)M) amitriptyline increased only the evoked tritium overfow while higher concentrations increased both evoked and resting overflow. 3 In the presence of atropine (1 X 10(-6 M) amitriptyline still produced an increase in evoked tritium overflow. 4 In the presence of a concentration of cocaine (1.1 X 10(-5) M) which produced a maximal blockade of the uptake of exogenous noradrenaline the application of amitriptyline still produced an increase in evoked tritium overflow. 5 In the presence of a concentration of phentolamine (1 X 10(-5) M) that produced complete blockade of the presynaptic alpha-adrenoceptors, amitriptyline still produced an increase in evoked tritium overflow. 6 In the presence of cocaine and phentolamine together the effect of amitriptyline on evoked overflow was abolished. 7 It is concluded that amitriptyline may raise synaptic levels of noradrenaline by blocking presynaptic alpha-adrenoceptors controlling noradrenaline release and by blocking its uptake into sympathetic neurones.

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Acta Pharmacol Toxicol (Copenh). 1980 Mar;46(3):213-8.
Myocardial pharmacokinetics of amitriptyline and clomipramine in the isolated, perfused rabbit heart.

Nielsen-Kudsk F, Quist S.

The myocardial pharmacokinetics of amitriptyline and clomipramine were investigated in isolated rabbit hearts, which were perfused with a modified Krebs-Henseleit solution containing the equimolar concentrations 0.25 or 0.28 micrograms ml-1 of the compounds, respectively. The rate of myocardial uptake of the drugs as a function of time was indirectly followed by determinations of the concentrations of the compounds in fractional samples of the coronary output of perfusate. The time course of disposition of amitriptyline from the myocardium was similarly followed after changing from amitriptyline perfusion to perfusion with drug-free liquid. The amitriptyline accumulation and disposition processes were found to fit bi-exponential functions indicating myocardial two-compartment characteristics of the compound. Clomipramine did only exhibit one-compartment myocardial characteristics. The biological half-life of amitriptyline in the myocardium was about 37.7 min. and a pronounced cardiac accumulation of about 340 micrograms of the compound at steady state was evidenced. The myocardial half-life of clomipramine was about 106 min. and the accumulated amount at steady state was calculated to be 1055 micrograms. After amitriptyline perfusion an increase in the pharmacokinetic rate constants k10 and k12 and a decrease in the apparent central volume of distribution was observed.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7361577&dopt=Abstract Elavil amitriptyline