Digoxigenin

390.51

390.51

216-806-2

NQ1SX9LNAU

DTXSID6051778

Prisms from ethyl acetate

87

1.1

1.0639 (rough estimate)

222 °C

435.71°C (rough estimate)

203ºC

1.6120 (estimate)

soluble in ethanol and methanol; slightly soluble in chloroform

Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.

8.41X10-15 mm Hg at 25 °C (est)

Henry's Law constant = 2.29X10-11 atm-cu m/mol at 25 °C (est)

195.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Prismatic rods from dilute alcohol; anhydrous as stout prisms from ethyl acetate; MP: 222 °C; Specific optical rotation = +27 deg at 20 °C/546 °C (c = 1.77 in methanol); although a 3beta-alcohol, it is not precipitated by digitonin /Digoxigenin dihydrate/|Prisms from dilute methanol; MP: 222-223 °C; Specific optical rotation = +61.3 deg at 20 °C/546 °C (c = 2 in methanol) /3,12-Diacetlydigoxigenin

II

6.1(a)

UN 2811 6.1/PG 1

3

26/27/28

36/37/39-45

FH5390000

T+

Stable under recommended storage conditions.

P260-P264-P280-P284-P302 + P350-P310

H300-H310-H330

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

|Danger|H300 (100%): Fatal if swallowed [Danger Acute toxicity, oral]|P260, P262, P264, P270, P271, P280, P284, P301+P310, P302+P350, P304+P340, P310, P320, P321, P322, P330, P361, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H300: Fatal if swallowed [Danger Acute toxicity, oral]

Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self-contained breathing apparatus for fire fighting if necessary.

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.|Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Digoxigenin was tested for but not detected, in downgradient groundwater sites impacted by leachate from the Norman Landfill, Norman, OK, sampled in 2000; detection limit = 0.008 ug/L(1). Digoxigenin was below the detection limit of 4.4 ng/L in outflow samples from the South Shore Water Reclamation Facility and the Jones Island Water Reclamation Facility, Milwaukee, WI. The compound was detected at concentrations of 4.9 and 9.2 ng/g in sediments impacted by the Jones Island Water Reclamation Facility outflow and South Gap (3.2 km south of out flow), respectively(2).

SEDIMENT: Digoxigenin was below the detection limit of 4.4 ng/L in Lake Michigan sediment samples, sampled on May 15, 2009 and April 9, 2010. Sediments were collected at a depth at 5 m and up to 3.6 km away from the South Shore Water Reclamation Facility, Milwaukee, WI(1). Digoxigenin was not detected in 30 samples of marine sediments from Bellingham Bay, Puget Sound, Washington, USA, sampled in April and June 2010(2).

IDENTIFICATION AND USE: Digoxigenin is a metabolite of digoxin and it can be produced by hydrolysis of digoxin. HUMAN STUDIES: All cardiac glycosides and their genins exhibited greater than 100-fold higher toxicity towards cultured human and monkey cells in comparison to the cell lines of mouse, Syrian hamster, and Chinese hamster origins. ANIMAL STUDIES: A possibility that intracellular Na+ ions available to Na+, K+-adenosine triphosphatase influence the action of digoxigenin to cause sodium-pump inhibition and a positive inotropic effect was examined with isolated left atria of guinea-pig hearts. The positive inotropic action of digoxigenin developed more rapidly when atria were stimulated at 3 Hz than at 1.5 Hz. The rate of development of the positive inotropic action was dependent on the frequency of membrane depolarizations rather than on contractions. Sodium pump activity, as estimated from ouabain-sensitive 86Rb uptake, was inhibited by digoxigenin in a concentration-dependent manner in quiescent atria. The inhibition was enhanced by electrical stimulation which shifted the concentration-inhibition curves to the left. The sensitivity of the sodium pump for digoxigenin was also affected by membrane depolarizations, suggesting a role for intracellular Na+. These data indicate that similar to the cardiac glycosides, the interaction of the aglycone with Na+,K+-adenosine triphosphatase is essential for the development of the positive inotropic action of this agent.

Both the competition of ethanol with cardiac sterols and the narrow margin of safety in the therapeutic use of digitalis derivatives would seem to place at increased risk those individuals who receive digitalis and simultaneously consume large amounts of ethanol or whose alcohol dehydrogenase function is impaired.

Both the competition of ethanol with cardiac sterols and the narrow margin of safety in the therapeutic use of digitalis derivatives would seem to place at increased risk those individuals who receive digitalis and simultaneously consume large amounts of ethanol or whose alcohol dehydrogenase function is impaired.

Digoxigenin is a metabolite of digoxin(1,2). Digoxin production and administration as a human and veterinary cardiotonic(2) may result in the release of digoxigenin to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3500(SRC), determined from a structure estimation method(2), indicates that digoxigenin is expected to have slight mobility in soil(SRC). Volatilization of digoxigenin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.3X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Digoxigenin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.4X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3500(SRC), determined from a structure estimation method(2), indicates that digoxigenin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.3X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 2.5(SRC), from its log Kow of 1.10(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2018).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), digoxigenin, which has an estimated vapor pressure of 8.4X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase digoxigenin may be removed from the air by wet and dry deposition(SRC). Digoxigenin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Digoxigenin is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(2). Digoxigenin does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 2.5 was calculated in fish for digoxigenin(SRC), using a log Kow of 1.10(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of digoxigenin can be estimated to be 3500(SRC). According to a classification scheme(2), this estimated Koc value suggests that digoxigenin is expected to have slight mobility in soil(SRC).

The Henry's Law constant for digoxigenin is estimated as 2.3X10-11 atm-cu m/mole(SRC) developed using a fragment constant estimation method(1). This Henry's Law constant indicates that digoxigenin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Digoxigenin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.4X10-15 mm Hg(SRC), determined from a fragment constant method(1).

DRINKING WATER: Digoxigenin was tested for but not detected in 24 samples of stream, raw, settled, filtered and finished water from a conventional US drinking water treatment plant sampled during November and December, 2001; reporting level = 0.008 ng/L(1).|SURFACE WATER: Digoxigenin was not detected in streams susceptible to contamination in the United States, sampled from 1999 to 2000; reporting level = 0.008 ug/L(1). Digoxigenin was below the detection limit of 4.4 ng/L water samples from Lake Michigan, sampled on May 15, 2009 and April 9, 2010. Samples were collected up to 3.6 km away from the South Shore Water Reclamation Facility, Milwaukee, WI(2).

Occupational exposure should be low or non-existent since digoxigenin is not produced in the US. The general public is not likely to be exposed to digoxigenin unless by direct medical treatment with the parent drug digoxin. (SRC)

A method was developed for the specific determination of digoxin and digitoxin, as well as their semisynthetic derivatives and dependent cardioactive metabolites, in autopsy samples of heart and kidney. A collective of 6 patients on long-term treatment with therapeutic doses of beta-acetyldigoxin had a mean myocardial digoxin content of 46.1 +/- 25.0 ng/g (SD); kidney: 50.3 +/- 30.3 ng/g. Digoxigenin bisdigitoxoside represented the second most important metabolite in heart and kidney; digoxigenin monodigitoxoside and digoxigenin follow, respectively. In a collective of seven patients on maintenance treatment with digitoxin, the mean tissue levels were higher but the metabolic pattern was similar (myocardial digitoxin content: 78.9 +/- 38.4 ng/g, renal content: 104.1 +/- 44.1 ng/g). The amount of digoxin formed by hydroxylation under long-term treatment with digitoxin in heart and kidney were approx 10 ng/g. A case of digoxin intoxication differed both in the tissue content and in the metabolic distribution.

In vitro metabolism of digoxin and its cleavage-related compounds was investigated using hepatocytes in primary culture and microsomal fractions both isolated from human livers. On these models, digoxin (DG3) and digoxigenin bisdigitoxoside (DG2) were not shown to be significantly metabolized in vitro ... Therefore, it appeared that the stepwise cleavage of DG3 and DG2 sugars was not cytochrome P450 dependent. This enzymatic system probably plays a minor role in humans for this particular reaction. However, digoxigenin monodigitoxoside (DG1) and digoxigenin (DG0) which are known to be formed after intra-gastric hydrolysis of DG3, were extensively converted to polar compounds (mainly glucuronides). In addition, using human liver microsomes, a wide variability in UDP-glucuronyl transferase (UDPGT) activities responsible for DG1 glucuronidation was demonstrated. These results suggest that two main factors may contribute to the overall interindividual variability of digoxin biotransformation: 1), the individual intra-gastric pH which influences the sugar cleavage leading to DG1 and DG0; ii), a variability in the level of the hepatic UDPGT specific for digitalis compounds conjugation.|Digoxigenin (I) biotransformation was investigated in 2 healthy men following ingestion of labeled (7.5 ug) and unlabeled (3 mg) I. Of the radioactivity in serum at 30 min, <26% chromatographed with I; the rest chromatographed as metabolites, most of which were polar. The main polar metabolites identified were glucuronides of 3-epidigoxigenin. There was extensive cross reactivity between metabolites and antisera to digoxin.|The sequential metabolism of digoxin (Dg3) to digoxigenin bis-digitoxoside (Dg2), digoxigenin mono-digitoxoside (Dg1) and digoxigenin (Dg0) was investigated in rat liver microsomes. Kinetic studies produced results consistent with a single enzyme mechanism describing the successive oxidative cleavages. Formation of Dg2 was catalysed with mean (+/-SD) Km and Vmax of 125 +/- 22 uM and 362 +/- 37 pmol/min/mg protein, respectively. The corresponding values for the formation of Dg1 were 61 +/- 5 microM and 7 +/-1 pmol/min/mg protein. Dg0 formation was catalysed with the apparent values of 30 +/- 9 uM and 310 +/- 30 pmol/min/mg protein. Chemical inhibition of cytochrome P450 (CYP) 3A subfamily with ketoconazole and triacetyoleandomycin decreased the formation of Dg2 and Dg1 by up to 90%. Antibodies specific to rat CYP3A2 lowered the rate of oxidative cleavage of Dg3 and Dg2 by up to 85%. Inhibition of CYP2E1, CYP2C subfamily and CYP1A2 by chemical and immuno-inhibition did not affect initial rates of metabolism of Dg3 and Dg2. In contrast, Dg1 metab was not affected by triacetyloleandomycin as well as by antibodies to CYP3A2, CYP2C11, CYP2E1, CYP2B1/2B2 and CYP1A2. It was however inhibited by >80% by gestodene and 17alpha-ethynylestradiol (selective inhibitors of human CYP3A). Collectively, these data support the involvement of CYP3A in the cleavage of Dg3 and Dg2 in rat liver microsomes. The enzyme-metabolizing Dg1 remains to be identified.|Human liver alcohol dehydrogenase (alcohol: NAD" oxidoreductase, EC 1.1.1.1) catalyzes the oxidation of the 3 beta-OH group of digitoxigenin, digoxigenin, and gitoxigenin to their 3-keto derivatives. Human liver alcohol dehydrogenase is the NAD(H)-dependent liver enzyme specific for the free hydroxyl group at C3 of the cardiac genins; this hydroxyl is the critical site of the genins' enzymatic oxidation and concomitant pharmacological inactivation in humans. Several kinetic approaches have demonstrated that ethanol and the pharmacologically active components of the digitalis glycosides are oxidized with closely similar kcat/Km values at the same site on human liver alcohol dehydrogenase, for which they compete. Human liver alcohol dehydrogenase thereby becomes an important biochemical link in the metabolism, pharmacology, and toxicology of ethanol and these glycosides, structurally unrelated agents that are both used widely.

The effect of potassium on the binding of digoxin or digoxigenin to isolated Na+, K+-ATPase was compared with that of potassium on the positive inotropic action of the agents in guinea-pig hearts. The binding of digoxigenin to the enzyme in vitro was reduced to a greater extent by potassium than was the binding of digotoxin. The digoxigenin-induced incr in the force of contraction of left atrial preparations estimated at steady state was reduced at higher potassium concns. Potassium had a lesser effect when digoxin was used as the inotropic agent. In contrast, potassium reduced the rate of development and also the rate of loss of the positive inotropic action of digoxin observed with left atrial and Langendorff preparations, respectively, to a greater extent than those of digoxigenin. The loss of the positive inotropic effect was more rapid with digoxigenin than with digoxin at each KCl concn. These data support the contention that the extent of the interaction of digitalis with Na+,K+-ATPase determines the degree of the positive inotropic effect.

Emergency and supportive measures. 1. Maintain on open airway and assist ventilation if necessary. 2. Monitor the patient closely for at least 12-24 hours after significant ingestion because of delayed tissue distribution. 3. Treat hyperkalemia with digoxin-specific antibodies; calcium (calcium gluconate 10% ... sodium bicarbonate ... and/or sodium polystyrene sulfonate (Kayexalate ... . a. NOTE: Although it is widely recommended that calcium be avoided inpatients with cardiac glycoside toxicity because of concern that it will worsen ventricular arrhythmias, this warning is based on old and very weak case reports and is not substantiated by animal studies. Calcium is the drug of choice for life-threatening cardiac toxicity due to hyperkalemia. b. Mild hyperkalemia may actually protect against tachyarrhythmias. 4. Hypokalemia and hypomagnesemia should be corrected, as these may contribute to cardiac toxicity. 5. Treat bradycardia or heart block with atropine, ... . temporary transvenous cardiac pacemaker amy be needed for persistent symptomatic bradycardia, but because a pacemaker may trigger serious arrhythmias in patients with digitalis toxicity, pacing is recommended only after failure or unavailability of digoxin-specific antibodies. 6. Ventricular tachyarrhythmias may respond to correction of low potassium or magnesium. Lidocaine and phenytoin have been used, but digoxin-specific antibody is the preferred treatment for life-threatening arrhythmias. Avoid quinidine, procainamide, and other type 1a or 1c antiarrhythmic drugs. /Digoxin and other cardiac glycosides/|Specific drugs and antidotes. Fab fragments of digoxin-specific antibodies (eg, DigiFab) are highly effective in reversing digoxin toxicity and are indicated for significant poisoning. This includes hyperkalemia (>mEq/L), symptomatic arrhythmias, high degree AV block, ventricular arrhythmias, and hemodynamic instability. Digoxin antibodies should also be considered in digoxin-toxic patients with renal failure and for prophylactic treatment in a patient with massive oral overdose and high serum levels. Digoxin antibodies rapidly bind to digoxin and, to a lesser extent, digitoxin and other cardiac glycoside. The inactive complex that is formed in excreted rapidly in the urine. ... /Digoxin and other cardiac glycosides/|Decontamination. Administer activated charcoal orally 9if conditions are appropriate. Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. /Digoxin and other cardiac glycosides/|Enhanced elimination. 1. Because of its large volume of distribution, digoxin is not effectively removed by dialysis or hemoperfusion. Repeat-dose activated charcoal or cholestyramine may be useful in patients with severe renal insufficiency, in whom clearance of digoxin is markedly diminished. ... /Digoxin and other cardiac glycosides/|For more Antidote and Emergency Treatment (Complete) data for Digoxigenin (7 total), please visit the HSDB record page.

/ALTERNATIVE and IN VITRO TESTS/ The relative toxicity of numerous cardiotonic steroids, including digoxigenin towards a number of independent cell lines established from human, monkey, mouse, Syrian hamster, and Chinese hamster have been determined. All cardiac glycosides and their genins, as well as the cardiotonic alkaloid cassaine, exhibited greater than 100-fold higher toxicity towards cultured human and monkey cells in comparison to the cell lines of mouse, Syrian hamster, and Chinese hamster origins. These differences are species-related as all cell lines (both normal as well as transformed) from any one species, as well as cells from the closely related species (e.g., man and monkey or mouse, Chinese hamster, and Syrian hamster), showed similar sensitivity towards these drugs. The observed species-related differences are highly specific for cardiotonic steroids.

Digoxigenin

Method: EPA-OW/OST 1694; Procedure: high performance liquid chromatography combined with tandem mass spectrometry; Analyte: digoxigenin; Matrix: water, soil, sediment, and biosolids; Detection Limit: 5.7 ng/L.|A post-column on-line immunochemical detection system was utilized for a very selective and sensitive method for determination of digoxin and digoxigenin. Fluorecine-labeled antibodies are used to target the chosen analytes, and the fluorescence detection system provides detection limits of 200 and 50 fmol, respectively, for digoxin and digoxigenin.

Lipids -> Sterol Lipids [ST] -> Sterols [ST01] -> Cardanolides and derivatives [ST0112]