Absorption, Distribution and Excretion
In animal studies highest concentrations were found in the liver, lungs, kidneys and spleen. /pyrrolizidine alkaloids/
After injection, radioactivity was rapidly excreted in the urine and feces (84% or greater) within 16 hr. The liver contained over 1.5% of the dose at 16 hr. A small amount, 0.04%, of the dose was transferred into the milk in 16 hr; the majority of radioactivity was found in the skim-milk fraction, suggesting that the /pyrrolizidine alkaloids/ were transferred to the milk as water-soluble metabolites. ...The binding to calf thymus DNA and microsomal macromolecules was measured in vitro. The binding was diminished in the absence of O2 or a NADPH-generating system or by boiling the microsomes. No inhibition of the binding by /potassium cyanide/ was observed. /Pyrrolizidine alkaloids/
...To investigate the transfer into cow's milk, a single dose of 1 mg of (3H)seneciphylline/kg of body weight was given orally to a dairy cow. The appearance of radioactivity derived from this compound was monitored in the blood and milk. Calculated as seneciphylline, over 100 ng/mL was found in the blood during the first 18 hr. After 54 hr, 11 ng/mL was still present. Alkaloid levels were similar in milk. After 64 hr, the concentration was still at 5 ng/mL. In total 0.16% of the dose was excreted in the milk. In the liver, 40 ng/g (0.06% of the dose) was found 3 weeks after treatment. In addition to unchanged seneciphylline and retronecine, N-oxides were detected in milkas metabolites (11.2% at 27 hr).

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Metabolism / Metabolites
In general, hepatotoxic pyrrolizidine alkaloids are metabolized in rat liver to give hydrolysis products, n-oxides and dehydropyrrolizidine (pyrrolic) deriv. ... Dehydroalkaloids are highly reactive alkylating agents... /pyrrolizidine alkaloids/
Dehydroretronecine...water-soluble pyrrolic metabolite of...seneciphylline...has been shown to be carcinogenic. /pyrrolizidine alkaloids/
In animals, the major metabolic routes of pyrrolizidine alkaloids are: (a) hydrolysis of the ester groups; (b) N-oxidation; and (c) dehydrogenation of the pyrrolizidine nucleus to pyrrolic derivatives. Routes (a) and (b) are believed to be detoxification mechanisms. Route (c) leads to toxic metabolites. Route (a) occurs in liver and blood; routes (b) and (c) are brought about in the liver by the microsomal mixed function oxidase system. /pyrrolizidine alkaloids/

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Biological Half-Life
Within a few hours, only a relatively small proportion of the administered dose remains in the body. Much of this is in the form of metabolites bound to tissue contents. A pyrrolizidine N-oxide disappeared from the serum after IV administration in animals, with initial half-lives of 3 -20 minutes. /pyrrolizidine alkaloids/

Non-Human Toxicity Values
LD50 Mouse iv 90 mg/kg
LD50 Rat iv 80 mg/kg
LD50 Rat (male) ip 77 mg/kg, 95% CONFIDENCE LIMITS 71-86 MG/KG
LD50 Rat (female) ip 83 mg/kg, 95% CONFIDENCE LIMITS 77-90 MG/KG.

[1]. Cytotoxicity of Senecio in macrophages is mediated via its induction of oxidative stress. Res Vet Sci. 2009 Aug;87(1):85-90.

[2]. Effect of seneciphylline and senecionine on hepatic drug metabolizing enzymes in rats. J Ethnopharmacol. 1984 Dec;12(3):271-8.

Seneciphylline is a white powder. (NTP, 1992)
LSM-2853 is a citraconoyl group.
Seneciphylline has been reported in Jacobaea carniolica, Senecio rodriguezii, and other organisms with data available.

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Mechanism of Action
The activation of the alkaloids by mixed-function oxidases leads to pyrrolic dehydro-alkaloids which are reactive alkylating agents. The liver necrosis results from binding of the metabolites with the liver cell. Some metabolites are released into the circulation and are believed to pass beyond the liver to the lung causing vascular lesions. The pyrrolic metabolites are cytotoxic and act on the hepatocytes and on the endothelium of blood vessels of the liver and lung. /pyrrolizidine alkaloids/
The effect of oral administration of the pyrrolizidine alkaloids, seneciphylline... from Senecio vulgaris (Compositae) on activities of hepatic epoxide hydrase, glutathione-S-transferase, aminopyrine-N-demethylase and arylhydrocarbon hydroxylase (AHH) was investigated in microsomes of young male albino rats. Seneciphylline significantly increased the activities of epoxide hydrase and glutathione-S-transferase but caused reduction of cytochrome P-450 and related monooxygenase activities. ...Seneciphylline... could not produce any prominent in vitro effect on the hepatic drug metabolizing enzymes under study, except slight stimulation of epoxide hydrase activity by both the alkaloids and slight reduction of aminopyrine demethylase activity by senecionine.

C18H23NO5

333.3789

333.157

480-81-9

5281750

White to off-white solid

1.3±0.1 g/cm3

577.7±50.0 °C at 760 mmHg

217ºC

303.2±30.1 °C

0.0±3.6 mmHg at 25°C

1.581

0.81

1

6

0

24

650

3

O1C(/C(=C(/[H])\C([H])([H])[H])/C([H])([H])C(=C([H])[H])[C@](C([H])([H])[H])(C(=O)OC([H])([H])C2=C([H])C([H])([H])N3C([H])([H])C([H])([H])[C@]1([H])[C@]32[H])O[H])=O

FCEVNJIUIMLVML-QPSVUOIXSA-N

InChI=1S/C18H23NO5/c1-4-12-9-11(2)18(3,22)17(21)23-10-13-5-7-19-8-6-14(15(13)19)24-16(12)20/h4-5,14-15,22H,2,6-10H2,1,3H3/b12-4-/t14-,15-,18-/m1/s1

(1R,4Z,7R,17R)-4-ethylidene-7-hydroxy-7-methyl-6-methylidene-2,9-dioxa-14-azatricyclo[9.5.1.014,17]heptadec-11-ene-3,8-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ~7.69 mg/mL (~23.07 mM)

Solubility in Formulation 1: ≥ 0.77 mg/mL (2.31 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 7.7 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: ≥ 0.77 mg/mL (2.31 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 7.7 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: ≥ 0.77 mg/mL (2.31 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 7.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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