Clin Biochem. 1976 Oct;9(5):247-51.
Estimation of amitriptyline and its metabolites in serum and urine by GLC using nitrogen-specific detector.

Gupta RN, Molnar G, Hill RE, Gupta ML.

1. A gas-chromatographic procedure for the estimation of amitriptyline and its metabolites in serum and urine using a nitrogen-specific detector is described. Specially cleaned glassware and purified solvents are used for the extraction of serum to further minimize extraneous peaks. Trimethylamine is added to serum before extraction to improve the recovery of drugs. Urine is refluxed at pH approximately 1 to hydrolyze the conjugates and to convert hydroxymetabolites to corresponding dehydro compounds. Serum is not hydrolyzed. 2. Two internal standards, one a tertiary amine similar in structure to amitriptyline and the other a secondary amine similar in structure to nortriptyline, are added to the specimen prior to extraction to obviate the need for accurate measurements of volumes during extraction and analysis. Urine and serum are washed with organic solvents at acidic pH to remove neutral and acidic impurities. Secondary bases are converted to their acetyl derivatives. 3. In the serum of a patient who is on amitriptyline therapy or who has ingested an overdose of amitriptyline, nortriptyline, a pharmacologically active metabolite is also measured. However, detection or estimation of hydroxymetabolites in serum is not clinically relevant. Hydroxylation index of an individual patient is determined by measuring the ratio of nortriptyline to its hydroxymetabolite in urine. 4. Amitriptyline and nortriptyline can be estimated in serum at a lower level of 10 and 20 ng/ml respectively. The procedure is linear over a wide range of amitriptyline and its metabolites. The use of an electronic integrator allows the estimation of different compounds with 100 fold difference in their concentration from the same chromatogram.

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Neuropharmacology. 1982 Jul;21(7):725-7.
Intact 5HT neuroterminals are not required for 5HT2 receptor down-regulation by amitriptyline.

Clements-Jewery S, Robson PA.

Chronic treatment of rats with the antidepressant, amitriptyline, resulted in a reduced number of cerebral cortical 5HT2 receptors measured as cinanserin displaceable [3H] spiperone binding. Pretreatment of rats with the serotonergic neurotoxin, p-chloroamphetamine, did not inhibit the effects of subsequent chronic amitriptyline treatment on 5HT2 receptor density whilst still severe neuroterminal destruction. It is suggested that such data indicate a post-synaptic locus of action for amitriptyline and have implications in regard to current concepts of antidepressant action.

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Pol J Pharmacol Pharm. 1989 May-Jun;41(3):247-51.
The effect of ethanol on arterial blood pressure, central venous pressure and ECG in rabbits treated with the single or multiple dose of amitriptyline or imipramine.

Polakowski P, Darzynkiewicz-Czernik D, Kubik-Bogucka E, Dzielska-Olczak M.

Department of Pharmacology, Medical Academy, Lodz, Poland.

Amitriptyline and imipramine given in the single dose insignificantly depressed the arterial blood pressure but significantly elevated the central venous pressure, prolonged the PQ interval and widened the QRS complex. After a prolonged daily treatment, the subsequent 21st dose of either antidepressant significantly depressed the arterial blood pressure; amitriptyline also depressed the central venous pressure. When given chronically, amitriptyline induced rhythm disturbances and the flattening of T-wave, while imipramine caused the widening of the QRS complex, block of the left bundle branch, changes in the T-wave amplitude, elevation in the ST interval. An intravenous infusion of ethanol potentiated those changes. The impairment of atrioventricular conduction occurred more frequently after administration of ethanol jointly with amitriptyline than with imipramine. Physostigmine salicylate elevated the depressed arterial blood pressure, aggravated the impairment of conduction and potentiated rhythm disturbances caused by the interaction of ethanol with antidepressants. In the above interactions with ethanol imipramine was less toxic than amitriptyline.

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Clin Pharmacol Ther. 1986 Apr;39(4):369-71.
Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers.

Mellstrom B, Sawe J, Bertilsson L, Sjoqvist F.

Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P less than 0.01) with all three parameters of amitriptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs = -0.89, -0.78, and -0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation.

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Pharmacol Biochem Behav. 1975 Nov-Dec;3(6):1063-7.
Effect of amitriptyline on avoidance learning in rats following olfactory bulb ablation.

Cairncross KD, King MG, Schofield SP.

It has been established that following bilateral olfactory bulb ablation there occurs a performance deficit in rats exposed to aversive learning procedures. Associated with the behavioral deficit, there occurs a reduction in total cortical norepinephrine (NE). If the behavioural deficit observed is a sequitur or correlate of the NE reduction, then drug therapy aimed at increasing NE availability in the cortex should overcome the reduction in performance. Amitriptyline increases NE availability by inhibiting uptake mechanisms and increases the rate of synthesis of NE. Rats, previously bulb ablated, were treated with amitriptyline over a 10 to 14 day period and tested in aversive situations. It was demonstrated that the drug treated rats showed improved performance early in acquisition, and that the performance improvement was maintained when the treatment period was extended to 14 days. These results indicate that amitriptyline was inducing a true pharmacological effect, and that the improved performance could be correlated with increased NE availability in the cerebral cortex.

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Br J Clin Pharmacol. 1984;17 Suppl 1:65S-68S.
Interaction between the beta-adrenoceptor blockers metoprolol and atenolol with amitriptyline and their effects on oxidative liver metabolism.

Kirch W, Spahn H, Kitteringham NR, Hutt HJ, Mutschler E, Ohnhaus EE.

Neither the kinetics of the hydrophilic beta-adrenoceptor blocker atenolol nor those of the lipophilic metoprolol were influenced by the concurrent administration of amitriptyline. Compared with placebo, chronic administration (14 days) of atenolol and metoprolol (each as monotherapy) did not significantly reduce oxidative liver metabolism as measured by antipyrine half-life and by 6-beta-hydroxycortisol excretion. Compared with atenolol and metoprolol monotherapy, chronic administration of amitriptyline concurrently with each of the beta-adrenoceptor blockers produced an insignificant decrease (circa 10-20%) in antipyrine half-life and 6-beta-hydroxycortisol excretion. Amitriptyline appears therefore to have little enzyme-inducing activity.

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Prog Neuropsychopharmacol. 1979;3(4):369-76.
Metabolic interaction between amitriptyline and perphenazine in psychiatric patients.

Cooper SF, Dugal R, Elie R, Albert JM.

Centre de recherches en sciences de la sante, Institut National de la Recherche Scientifique, Montreal.

1. Steady-state plasma level samples of sixty-five schizophrenic patients from two psychiatric hospitals assigned to three treatment groups (amitriptyline 150 mg/day, perphenazine 20 mg/day and a combination of amitriptyline and perphenazine at 150 mg and 20 mg/day) were assayed for amitriptyline (AT), endogenous nortriptyline (NT) and perphenazine (PPZ) using gas-liquid chromatography. 2. Results reveal that AT and NT levels are independent of sex and hospital environment. 3. PPZ significantly increased the steady-state NT plasma levels, probably through inhibition of the hydroxylation biotransformation pathway, but had no effect on AT levels, thus indicating that PPZ has no influence on the desmethylation pathway, or alternatively, the hydroxylation of AT.

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Neuropsychobiology. 1978;4(5):305-13.
Pharmacokinetic interaction between amitriptyline and neuroleptics.

Jus A, Gautier J, Villeneuve A, Jus K, Pires P, Gagnon-Binette M, Fortin C.

The influence of amitriptyline on the plasma level of various neuroleptics was studied in 25 chronic schizophrenic patients. The study lasted 20 weeks. Patients were kept first 4 weeks on their former neuroleptic medication, with amitriptyline added for 12 subsequent weeks, and withdrawn during the last 4 weeks when only the neuroleptic medication was continued unchanged. The plasma level of neuroleptics was assayed by gas-liquid chromatography, once weekly throughout the study. The amitriptyline plasma level was also evaluated once weekly during the 12 weeks of its administration. The mean neuroleptic plasma values for each 4-week period were pooled together in three groups: aliphatic, piperdine and piperazine phenothiazine derivatives. Amitriptyline provoked some increase of the plasma level of all phenothiazine derivatives. This augmentation was significant only transitorily, however. The putative mechanisms of this neuroleptic tricyclic antidepressant interaction are discussed.

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