Elimination and pharmacological effects following single oral doses of 50 and 75 mg of amitriptyline in man

Schulz, Pierre; Balant-Gorgia, A. E.; Kubli, A.; Gertsch-Genet, C.; Garrone, G

doi:10.1007/bf00342785

Cited by 4 publications

(3 citation statements)

References 4 publications

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“…N-demethylation of amitriptyline yields nortriptyline, an anti-depressant in its own right. Both amitriptyline and nortriptyline strongly bind to plasma proteins (Borga et al, 1969) and exhibit extensive tissue binding, evidenced by their high apparent volume of distribution (Schulz et al, 1983; Kornhuber et al, 1995; Lombardo et al, 2004). Further metabolization by CYP450 upon hydroxylation and glucoronidation results in inactivation followed by excretion in the urine (Rudorfer and Potter, 1987; summarized in Gillman, 2007).…”

Section: Amitriptylinementioning

confidence: 99%

Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons

et al. 2014

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Amitriptyline, a tricyclic antidepressant, has been used in the clinic to treat a number of disorders, in particular major depression and neuropathic pain. In the 1970s the ability of tricyclic antidepressants to inhibit acid sphingomyelinase (ASM) was discovered. The enzyme ASM catalyzes the hydrolysis of sphingomyelin to ceramide. ASM and ceramide were shown to play a crucial role in a wide range of diseases, including cancer, cystic fibrosis, diabetes, Alzheimer's disease, and major depression, as well as viral (e.g., measles virus) and bacterial (e.g., Staphylococcus aureus, Pseudomonas aeruginosa) infections. Ceramide molecules may act in these diseases by the alteration of membrane biophysics, the self-association of ceramide molecules within the cell membrane and the ultimate formation of larger ceramide-enriched membrane domains/platforms. These domains were shown to serve the clustering of certain receptors such as CD95 and may also act in the above named diseases. The potential to block the generation of ceramide by inhibiting the ASM has opened up new therapeutic approaches for the treatment of these conditions. Since amitriptyline is one of the longest used clinical drugs and side effects are well studied, it could potentially become a cheap and easily accessible medication for patients suffering from these diseases. In this review, we aim to provide an overview of current in vitro and in vivo studies and clinical trials utilizing amitriptyline to inhibit ASM and contemplate possible future applications of the drug.

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Section: Amitriptylinementioning

confidence: 99%

Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons

et al. 2014

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“…Relatively little was previously known about the quantitative importance of direct glucuronidation for the elimination of AT in man in vivo. Schulz et al (1983) reported that only 2-5% of the given dose of AT (50 or 75 mg) was recovered in urine as AT and its glucuronide. Interestingly, in the study of Vandel et al (1982), a wide interindividual variation in the recovery of AT as conjugate was observed, the AT conjugate accounting for 3.4 to 57.7% (mean 26%) of the total recovery in urine.…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation of Amitriptyline in Man in Vivo

Dahl‐Puustinen

Åberg‐Wistedt

Bertilsson

1989

Pharmacology & Toxicology

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The urinary excretion of amitriptyline (AT) as N-glucuronide was studied in healthy volunteers after single oral doses of AT and in patients on continuous treatment with AT. In the volunteers, 8 +/- 3% of a 25 mg dose of AT was recovered in urine as glucuronide during 108 hr. No difference between slow and rapid debrisoquine hydroxylators with respect to the excretion of AT glucuronide was seen. 0.08 to 1.68% of the given AT dose was recovered in urine in unchanged form. The excretion of unchanged AT correlated with the debrisoquine metabolic ratio (rs = 0.61; p less than 0.01). In 5 patients on continuous treatment with AT (125-150 mg/day), 8 +/- 5% of the daily dose was recovered in 24-hr urine as AT glucuronide. The present study shows that direct glucuronidation is a minor metabolic pathway of AT in man in vivo both after single low doses and during continuous treatment with therapeutic doses.

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“…Demethylation and hydroxylation are the major metabolic reactions (Bush and Harrier, 1983) and both amitriptyline and its first demethylation product, nortriptyline, accumulate in plasma during long-term treatment. However, only one published study has involved more than one dose level (Schulz et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Hypotension and bradycardia induced by amitriptyline in healthy volunteers

Curry

DeVane

Wolfe

1988

Human Psychopharmacology

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Seventeen healthy volunters in three groups received no treatment, or 25 or SO mg doses of amitriptyline. Maximal measured concentrations of amitriptyline occurred at 4 h post-dosage. There was a dose-dependent change i n performance of a digit symbol substitution test. Visual analogue scales measuring drowsiness, speed of thinking, and lethargy were sensitive to the drug. The low dose induced no blood pressure changes, but tachycardia occurred. The higher dose induced hypotension with bradycardia, a hitherto undocumented reaction to the drug.

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Elimination and pharmacological effects following single oral doses of 50 and 75 mg of amitriptyline in man

Cited by 4 publications

References 4 publications

Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons

Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons

Glucuronidation of Amitriptyline in Man in Vivo

Hypotension and bradycardia induced by amitriptyline in healthy volunteers

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