PC3 cells are cytotoxic to protriptyline hydrochloride (0-70 μM; 24 hours) [2].

Protriptyline hydrochloride (10 mg/kg; intraperitoneal injection; 21 days; AD rat model) improves spatial learning and retained memory in STZ-treated rats [3].

Cytotoxicity assay[2]
Cell Types: PC3 Cell
Tested Concentrations: 50, 60 and 70 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Cell viability diminished in a concentration-dependent manner.

Animal/Disease Models: AD rat model [3]
Doses: 10 mg/kg
Route of Administration: intraperitoneal (ip) injection; 21 days.
Experimental Results: diminished pTau, Aβ42 and BACE-1 levels, neurodegeneration, oxidative stress and glial activation. By reducing NFκB and GFAP expression, improving p-ERK/ERK ratio and increasing BDNF and CREB levels.

Absorption, Distribution and Excretion
Protriptyline is reported to undergo cumulative urinary excretion during 16 days, which accounts for approximately 50% of the total drug administered. The fecal excretion pathway seems to play a minimal role in drug elimination.
EXCRETION...IS RAPID, IN CONTRAST TO LONG LATENCY OF ONSET OF ACTION OF DRUGS. /TRICYCLIC ANTIDEPRESSANTS/
...WELL ABSORBED FROM GI TRACT. ... RAPIDLY DISTRIBUTED & METABOLIZED BY DEMETHYLATION, OXIDATION, & AROMATIC HYDROXYLATION. /IMIPRAMINE/
IN URINE OF RATS TREATED WITH PROTRIPTYLINE... THERE WAS TWICE AS MUCH 10,11-DIHYDRO-10,11-EPOXY-5-(3-METHYLAMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE AS 10,11-DIHYDRO-10,11-EPOXY-5-(3-AMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE EXCRETED &.../BOTH/ ACCOUNTED FOR 40% OF DOSE OF PROTRIPTYLINE.
MEAN PLASMA LEVELS FOR PROTRIPTYLINE IN PT ALSO ADMIN NITRAZEPAM INDISTINGUISHABLE FROM PT RECEIVING NO NITRAZEPAM. MEAN PLASMA LEVELS FOR PT RECEIVING SODIUM AMYLOBARBITONE SIGNIFICANTLY DECR. EARLY VALUES MAY BE OF PREDICTIVE IMPORTANCE TO PERMIT EARLY DOSE ADJUSTMENT.

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Metabolism / Metabolites
KNOWN OXIDATION OF 10,11 DOUBLE BOND OF PROTRIPTYLINE IN MAN, MINIATURE PIG, & DOG... 2 METABOLITES HAVE BEEN DETECTED WHICH DEMONSTRATE EPOXIDE INTERMEDIATE, NAMELY, DIHYDRODIOL & REARRANGEMENT PRODUCT WHOSE FORMATION IS...CATIONIC INTERMEDIATE...REARRANGING TO DIHYDROANTHRACENIC STRUCTURE.
IN DOGS, MINIATURE PIGS, & MAN, 3 URINARY METABOLITES HAVE NOW BEEN FOUND 10-HYDROXY-N-METHYL-5H-DIBENZO(AD)CYCLOHEPTENE-5-PROPYLAMINE, 10,11-DIHYDROXY-N-METHYL-5H-DIBENZO(AD)CYCLOHEPTENE-5-PROPYLAMINE & 5,10-DIHYDRO-10-FORMYLANTHRACENE-5-PROPYLAMINE.
...PROTRIPTYLINE...AFFORDS URINARY 10,11-OXIDE.
IN URINE OF RATS TREATED WITH PROTRIPTYLINE...2 METABOLITES HAVE BEEN IDENTIFIED...AS 10,11-DIHYDRO-10,11-EPOXY-5-(3-M ETHYLAMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE & 10,11-DIHYDRO-10,11-EPOXY-5-(3-AMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE.
Route of Elimination: Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.

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Biological Half-Life
AFTER A SINGLE ORAL DOSE OF 30 MG TO 8 SUBJECTS, PEAK LEVELS RANGED FROM 10.4-22.3 NG/ML, 6-12 HR AFTER ADMIN. MEAN T/2 WAS 74.3 HR & RANGED FROM 53.6-91.7 HR IN INDIVIDUAL SUBJECTS.
SINGLE ORAL DOSE OF HCL-SALT ADMIN TO 8 PERSONS. EST 1ST PASS METAB WAS RELATIVELY SMALL, 10-25% OF DOSE, ASSUMING COMPLETE ABSORPTION. MEAN VOL OF DISTRIBUTION 22.5 L/KG & RANGED FROM 15.0-31.2 L/KG. CONCLUSION WAS THAT LONG T/2 IS CORRELATED WITH SMALL 1ST PASS METABOLISM.
PLASMA LEVELS IN 30 PT. AFTER 3.5 WK TREATMENT @ 40 MG/DAY, PLASMA LEVELS RANGED FROM 430-1430 NMOL/L. SINGLE DOSE STUDIES IN 5 VOLUNTEERS SUGGEST THAT VOL OF DISTRIBUTION OF PROTRIPTYLINE SHOWS LITTLE INTERSUBJECT VARIATION. HOWEVER, T/2 MAY VARY, RANGING FROM 54-198 HR.

Hepatotoxicity
Liver test abnormalities have been reported to occur in 10% to 12% of patients on tricyclic antidepressants, 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. The rate of serum enzyme elevations specifically during protriptyline therapy has not been well defined. Rare instances of clinically apparent acute liver injury have been reported in patients on tricyclic antidepressants, but there have been no specific reports related to protriptyline. In typical tricyclic antidepressant acute liver injury, the latency to onset has ranged from 1 to 14 months. The pattern of serum enzyme elevations was typically cholestatic, but hepatocellular cases have also been reported including an acute hepatitis-like syndrome with acute liver failure. Instances of acute cholestatic hepatitis and prolonged jaundice compatible with vanishing bile duct syndrome have been linked to other tricyclic antidepressants, mostly amitriptyline and imipramine, the two most commonly used agents in this class. Signs or symptoms of hypersensitivity (rash, fever and eosinophilia) are frequent in reported cases, but these symptoms are usually mild and transient. Autoantibody formation is rare. Protriptyline is a rarely used tricyclic antidepressant but is suspected of having a profile of adverse effects similar to that of imipramine and amitriptyline.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because there is no published experience with protriptyline during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Published information on protriptyline was not found as of the revision date. Follow-up for 1 to 3 years in a group of 20 breastfed infants whose mothers were taking a tricyclic antidepressant found no adverse effects on growth and development. Two small controlled studies indicate that other tricyclic antidepressants have no adverse effect on infant development. In another study, 25 infants whose mothers took a tricyclic antidepressant during pregnancy and lactation were tested formally between 15 to 71 months and found to have normal growth and development.
◉ Effects on Lactation and Breastmilk
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking protriptyline.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

[1]. Molecular investigations of protriptyline as a multi-target directed ligand in Alzheimer's disease. PLoS One. 2014 Aug 20;9(8):e105196.

[2]. The mechanism of protriptyline-induced Ca2+ movement and non-Ca2+-triggered cell death in PC3 human prostate cancer cells. J Recept Signal Transduct Res. 2015;35(5):429-34.

[3]. Protriptyline improves spatial memory and reduces oxidative damage by regulating NFκB-BDNF/CREB signaling axis in streptozotocin-induced rat model of Alzheimer's disease. Brain Res. 2021 Mar 1;1754:147261.

Protriptyline is a carbotricyclic compound. It has a role as an antidepressant. It derives from a hydride of a dibenzo[a,d][7]annulene.
Protriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, protriptyline does not affect mood or arousal, but may cause sedation. In depressed individuals, protriptyline exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. In addition, TCAs down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H1 receptors, alpha1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Protriptyline may be used for the treatment of depression.
Protriptyline is a Tricyclic Antidepressant.
Protriptyline is a tricyclic antidepressant that was previously widely used in the therapy of major depression. Most of the tricyclic antidepressants have been shown to cause a low rate of mild and transient serum enzyme elevations and rare cases of clinically apparent acute cholestatic liver injury. The potential hepatotoxicity specifically of protriptyline, however, has not been well defined.
Protriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, protriptyline does not affect mood or arousal, but may cause sedation. In depressed individuals, protriptyline exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. In addition, TCAs down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H₁ receptors, α₁-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Protriptyline may be used for the treatment of depression.
Tricyclic antidepressant similar in action and side effects to IMIPRAMINE. It may produce excitation.
See also: Protriptyline Hydrochloride (has salt form).

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Drug Indication
For the treatment of depression.

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Mechanism of Action
Protriptyline acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).
ACTION OF TRICYCLIC ANTIDEPRESSANTS ON METAB OF CATECHOLAMINES & INDOLEAMINES IN BRAIN HAS CONTRIBUTED SIGNIFICANTLY TO "BIOGENIC AMINE HYPOTHESIS" OF DEPRESSION. ... /ALL/ BLOCK RE-UPTAKE OF NOREPINEPHRINE BY ADRENERGIC NERVE TERMINALS. /DEMETHYLATED ANALOGS ARE MORE POTENT IN THIS ACTION/ /TRICYCLIC ANTIDEPRESSANTS/

C19H22CLN

299.84

299.144

1225-55-4

Protriptyline;438-60-8;Protriptyline (N-methyl-d3) (hydrochloride);1435934-21-6

4976

White to off-white solid powder

407.7ºC at 760 mmHg

169-171°

198.3ºC

7.41E-07mmHg at 25°C

5.494

1

1

4

20

296

0

BWPIARFWQZKAIA-UHFFFAOYSA-N

InChI=1S/C19H21N/c1-20-14-6-11-19-17-9-4-2-7-15(17)12-13-16-8-3-5-10-18(16)19/h2-5,7-10,12-13,19-20H,6,11,14H2,1H3

N-methyl-3-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenyl)propan-1-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~833.78 mM)
H2O : ~100 mg/mL (~333.51 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (333.51 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)