It has been demonstrated that podofilox, a non-alkaloid lignan toxin, inhibits the growth of a range of molds. It is taken from the roots and rhizomes of the Podophyllum genus. A natural substance called podofilox prevents tubulin polymerization and has been used as a prototype for the creation of other anti-tumor medications intended for therapeutic application.

Absorption, Distribution and Excretion
No serum drug concentration was detected after topical application of 0.05 mL of 0.5% podophyllotoxin solution to the external genitalia. Peak serum drug concentrations of 1–17 ng/mL were reached within 1–2 hours after application of 0.1–1.5 mL. A small amount of podophyllotoxin may be absorbed systemically after topical application. In a study of adult patients with anogenital warts caused by human papillomavirus (HPV), no serum drug concentration was detected after topical application of 0.05 mL of 0.5% podophyllotoxin solution to the external genitalia; however, peak serum concentrations of 1–17 ng/mL were reached within 1–2 hours after topical application of 0.1–1.5 mL of solution. Metabolism/Metabolites Half-life: 1.0–4.5 hours. Biological half-life 1.0–4.5 hours. The serum elimination half-life of podophyllotoxin is estimated to be 1–4.5 hours.

Toxicity Summary
Identification: Podophyllum resin is a dermatological drug. Source: The dried resin of the roots and rhizomes of the North American variety Podophyllum peltatum (also known as Datura or May apple); the active ingredients are lignans, including podophyllotoxin (20%), α-podophyllin (10%), and β-podophyllin (5%). It is a light brown to yellowish-green solid powder, soluble in water, ethanol, chloroform, acetone, benzene, and glacial acetic acid. Indications: For the removal of warts or corns. Description: Podophyllum resin has antimitotic activity and is primarily used to treat anogenital warts (condyloma acuminata). Podophyllum resin has been used to treat external genital warts, perianal warts, and urethral warts, but not for the treatment of cervical or urethral warts. Care must be taken to avoid application to healthy tissue. Podophyllum resin is also used in ointments for the treatment of plantar warts. Podophyllotoxin was once used as a laxative, but its strong purgative effect after oral administration, coupled with its irritant effect on the intestinal mucosa and its inducing of violent intestinal peristalsis, has led to its replacement by less toxic laxatives. Human Exposure: Major Risks and Target Organs: The main active ingredient in podophyllotoxin is a lipid-soluble compound that readily crosses cell membranes. Podophyllotoxin and its derivatives are potent cytotoxic substances, inhibiting cell mitosis and DNA synthesis in a manner similar to colchicine. Cell division ceases, other cellular processes are impaired, ultimately leading to cell destruction and tissue necrosis. Topical podophyllotoxin is readily absorbed systemically and can cross the placental barrier. Both topical and oral application can produce multi-systemic toxicity. Clinical Manifestations Overview: Systemic toxicity manifestations include nausea and vomiting (which may persist), tachypnea, fever, coma, tachycardia, hypotension, paralytic ileus, oliguria, renal failure, leukocytosis, leukopenia, peripheral neuropathy, and death. Contraindications: Pregnancy: Topical podophyllotoxin can be absorbed systemically and cross the placental barrier. It is associated with the occurrence of congenital malformations in humans. Routes of exposure: Oral: Easily absorbed even if it causes nausea and vomiting. Skin: Can be absorbed systemically after topical application, especially when the skin surface is not intact. Eyes: Good absorption through mucous membranes. Routes of absorption: Oral absorption: Podophyllotoxin is rapidly and effectively absorbed after ingestion. In one fatal case, a patient accidentally ingested 10 to 11 grams of a 25% podophyllotoxin benzoin tincture solution in a doctor's office. He immediately took ipecac syrup and vomited 45 minutes later. The doctor also administered activated charcoal and magnesium citrate. Despite hemoperfusion, the patient died 39 hours after ingestion. Skin absorption: Several cases of systemic poisoning following topical application of podophyllotoxin have been reported in the literature. In these cases, the onset of symptoms was typically delayed by 2 to 24 hours. Distribution via exposure: Due to the water solubility of podophyllotoxin, its volume of distribution is expected to be small. Furthermore, no rebound effect was observed after hemoperfusion. Metabolism: No relevant data are currently available. In one case report, doctors measured the concentration of podophyllotoxin in the patient's plasma before, during, and after hemoperfusion. Before the start of hemoperfusion, the plasma concentration of podophyllotoxin decreased rapidly, suggesting rapid metabolism. Some case reports showed delayed symptom onset, possibly indicating that the metabolites of podophyllotoxin are more toxic than the toxin itself. This study detected one metabolite during hemoperfusion, but several other possible metabolites were identified during analysis, all of which were cleared by hemoperfusion. Mechanism of action: Toxoplasmosis: Podophyllotoxin is a potent spindle toxin whose mechanism of action in blocking metaphase of mitosis is similar to colchicine. Human poisoning is caused by topical application or ingestion of commercially available extracts. Overexposure can lead to neurotoxicity, gastrointestinal toxicity, and hematopoiesis, and occasionally death. In rare cases, ingestion of unripe fruit or plant parts can also cause poisoning, primarily manifesting as diarrhea. Ripe fruit is non-toxic. Podophyllotoxin is a keratolytic agent with corrosive and laxative effects. Podophyllotoxin is an antimitotic agent. It binds to tubulin, a protein subunit of the spindle microtubules, at the same or highly overlapping binding site as colchicine. The antimitotic effect of podophyllotoxin is likely due to interference with chromosome movement. Its molecular mechanism of blocking mitosis involves the binding of podophyllotoxin to tubulin, disrupting the microtubule structure of the mitotic spindle. Podophyllotoxin is corrosive, but its action differs from most corrosives; it is neither direct nor immediate: cell damage and tissue erosion occur slowly after cell division has ceased and other cellular processes are impaired. Human toxicity: Adults: Most cases of systemic poisoning due to topical application of podophyllotoxin occur in women, some of which are fatal. Extensive or excessive topical application of podophyllotoxin, or prolonged contact with the skin or mucous membranes, can lead to severe systemic toxicity. The risk of systemic toxicity may increase if podophyllotoxin is applied to easily bleeding warts, warts that have recently undergone biopsy, or accidentally applied to normal skin or mucous membranes surrounding the affected area. Podophyllum resin can cause renal failure and hepatotoxicity (elevated serum lactate dehydrogenase (LDH), aspartate aminotransferase (AST; SGOT), and alkaline phosphatase levels) after topical application or ingestion. Podophyllum resin can cause severe systemic toxicity; both topical application and ingestion can lead to such toxic reactions. Toxicity is usually reversible, but can be fatal in some cases. Children: Children appear more susceptible to fever and seizures. Most reported cases are accidental ingestion. Carcinogenicity: Podophyllum resin is suspected to be a human carcinogen. Teratogenicity: Podophyllum resin may have teratogenic effects in humans. At least two cases of possible teratogenicity from podophyllum resin have been reported. Interactions: Other keratolytic agents may irritate the skin and increase the absorption of podophyllum resin. Major adverse reactions: The risk of systemic toxicity may be increased when podophyllum resin is applied to fragile, bleeding, or recently biopsied skin. Adverse reactions may occur when warts are present, or when the drug is accidentally applied to normal skin or mucous membranes surrounding the affected area. Neurological adverse reactions may occur after topical application of podophyllum resin; these reactions usually have a late onset and prolonged duration. Topical application of podophyllotoxin may cause encephalopathy (manifested as altered consciousness, ranging from mild confusion to coma), lasting 7 to 10 days, during which time electroencephalography (EEG) may show generalized slow waves. The following side effects/adverse reactions were selected based on their potential clinical significance: Rash or itching: Hypersensitivity to benzoin, which may be present in some formulations. History of skin redness, burning, or other irritation. Abdominal pain, nausea, or vomiting. Diarrhea, sometimes severe and prolonged. Clumsiness or unsteady gait. Confusion and impaired reflexes. Excitement, irritability, nervousness, and hallucinations. Muscle weakness, leukopenia (sore throat and fever), and thrombocytopenia; autonomic neuropathy (difficulty or pain in urination; dizziness or vertigo, especially when rising from a lying or sitting position; rapid heartbeat); dyspnea; somnolence; paralytic ileus (constipation, nausea, and vomiting; upper abdominal or stomach pain, mild and persistent dull pain); peripheral neuropathy (numbness, tingling, pain, or weakness in the hands or feet). Peripheral neuropathy typically appears about 2 weeks after podophyllin use, may gradually worsen over up to 3 months, and may persist for up to 9 months or longer. Seizures have been reported. Clinical manifestations: Acute poisoning: Ingestion: Ingestion may cause: nausea and vomiting, which may be severe and persistent, and occur rapidly after ingestion. Abdominal pain, intestinal obstruction (paralytic), drowsiness. Coma, tachypnea, respiratory failure, tachycardia, hypotension, arrhythmia, cardiovascular failure, oliguria, renal failure, fever, metabolic acidosis, leukocytosis, leukopenia, thrombocytopenia, pancytopenia, peripheral neuropathy, death. Skin contact: Unlike ingestion, symptoms after skin contact may be delayed up to 24 hours. These symptoms are similar to those after ingestion. Eye contact: Podophyllin can be absorbed through this route, but severe systemic poisoning is rare. Local irritation and corneal and conjunctival damage may occur. Chronic poisoning: Ingestion: This type of poisoning occurs when podophyllin is used as a laxative or weight-loss drug. No related reports have been found in recent years. In such cases, diagnosis of poisoning is sometimes difficult due to the different clinical presentation compared to acute poisoning. Initial clinical symptoms may include hematologic symptoms, gastrointestinal symptoms, or peripheral neuropathy. Skin exposure: Repeated topical treatment of warts or condyloma acuminata can lead to systemic poisoning or local skin damage (erosion, pain, bleeding, infection). Course, prognosis, and cause of death: The exact course of illness after overdose is difficult to predict because we rarely have accurate knowledge of the absorbed dose. It is noteworthy that some patients with severe poisoning (especially children) survive, while others die or develop permanent sequelae (peripheral neuropathy) even after ingesting lower doses. Death is usually caused by complications affecting the brain, cardiovascular system, kidneys, or hematologic system. Systemic description of clinical effects: Cardiovascular system: tachycardia, cardiac arrhythmias, hypotension, and cardiovascular failure. Respiratory system: tachypnea and respiratory failure. Pneumonia (similar to chemical pneumonia) and pulmonary edema (rare). Nervous system: Central nervous system (CNS): confusion, drowsiness, coma, and seizures. Peripheral nervous system: Peripheral neuropathy, which can develop within days and may take weeks or months to resolve. Permanent sequelae may remain. Autonomic nervous system: Paralytic ileus. Skeletal and smooth muscle: Rhabdomyolysis may be accompanied by myoglobinuria. This may worsen kidney failure. CPK should be monitored. Gastrointestinal tract: Nausea and vomiting, which may be persistent and severe; abdominal pain; paralytic ileus and diarrhea, which may lead to water and electrolyte imbalances. Liver: Elevated liver enzymes. Urinary system: Kidneys: Oliguria and renal insufficiency. Other: Cystitis and painful urination. Endocrine and reproductive system: Fetal death, miscarriage, premature birth, and fetal malformations. Skin: Itching around the treatment site, especially if the skin is not protected with petroleum jelly. Irritation, urticaria, skin necrosis, and bleeding. Scarring, especially in the anogenital area; paraphimosis, which may require circumcision; and pseudoepithelial hyperplasia. Eyes, ears, nose, and throat: Local reactions: skin or mucous membrane irritation, necrosis, tissue scarring, hemorrhage, and corneal erosion. Hematologic system: Leukocytosis, followed by leukopenia, anemia, thrombocytopenia, and pancytopenia. Special risks: Podophyllotoxin is contraindicated in pregnant or lactating women. Animal studies: Mutagenicity: Podophyllotoxin is mutagenic to Salmonella Typhimurium. /Podophyllotoxin/
Etoposide is a semi-synthetic derivative of podophyllotoxin that inhibits DNA breakage induced by topoisomerase II. The drug has the highest activity in late S phase and early G2 phase of the cell cycle. Teniposide is an analog with very similar pharmacological properties. Podophyllotoxin derivatives exhibit binding activity against topoisomerase II in late S phase and early G2 phase. For example, etoposide binds to and stabilizes transient breaks induced by this enzyme, disrupting break repair in double-stranded DNA, thereby preventing DNA unwinding and replication. Mutants resistant to podophyllotoxin or its topoisomerase II inhibitor derivatives, such as etoposide (VP-16), have been identified in Chinese hamster cells. The mutually exclusive cross-resistance patterns of these mutants provide a highly specific method for distinguishing between the two podophyllotoxin derivatives. A protein called P1 is affected in podophyllotoxin-resistant Chinese hamster mutant cells; this protein was later identified as mammalian HSP60 or a molecular chaperone protein. (Wikipedia)

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Non-human toxicity values
Rat intravenous LD50 8.7 mg/kg
Rat intraperitoneal LD50 15 mg/kg

[1]. Proteomic changes induced by podophyllotoxin in human cervical carcinoma HeLa cells. Am J Chin Med. 2013;41(1):163-75.

[2]. Analgesic and anti-inflammatory activity of podophyllotoxin derivatives. Pharm Biol. 2013 Jan 31.

[3]. Biochemical composition and antioxidant capacity of extracts from Podophyllum hexandrum rhizome. BMC Complement Altern Med. 2012 Dec 22;12:263.

[4]. Podophyllotoxin and nocodazole counter the effect of IKP104 on tubulin decay. J Protein Chem. 1998 Oct;17(7):663-8.

[5]. Podophyllotoxin.

Podophyllotoxin is an organic heterotetracyclic compound with a furanodioxane skeleton and 3,4,5-trimethoxyphenyl substituents. It is found in the roots and rhizomes of plants in the Podophyllum genus and is used topically to treat genital warts. Podophyllotoxin possesses various effects, including antitumor activity, keratolytic activity, tubulin regulation, microtubule depolymerization, antimitotic activity, and phytometabolic activity. It is a furanodioxane compound, belonging to the lignan class and organic heterotetracyclic compounds. Podophyllotoxin is a prescription drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of genital and perianal warts. Podophyllotoxin gels and solutions are for external use only. Genital and perianal warts are caused by human papillomavirus (HPV). HPV may be an opportunistic infection (OI) of HIV. Podophyllotoxin is a lignan found in the resin of the Podophyllum plant roots. It is a potent spindle toxin, toxic when ingested, and was once used as a laxative. It is highly irritating to the skin and mucous membranes, has keratolytic effects, and has been used to treat warts and keratosis. It may also possess antitumor properties, as do some of its homologues and derivatives. The physiological action of podophyllotoxin is achieved by reducing mitosis. Podophyllotoxin has been reported in Phialocephala fortinii, Dysosma aurantiocaulis, and other organisms with relevant data. Podophyllotoxin is the pure, stable form of podophyllin resin, containing only the biologically active portion of the compound. Podophyllotoxin is a toxic polycyclic antimitotic agent, primarily isolated from the rhizomes of Podophyllum peltatum. This drug is for external use. (NCI04) Podophyllotoxin is a lignan (or lignan compound) found in the podophyllin resin of the roots of the Podophyllum plant. It is a potent spindle toxin, toxic when ingested, and was once used as a laxative. It is highly irritating to the skin and mucous membranes, has keratolytic effects, and was used to treat warts and keratosis. It may also possess antitumor properties, as some of its homologues and derivatives also exhibit these properties.
Polypodophyllin is a lignan (or lignan compound) found in the resin of the root of the Podophyllum plant. It is a potent spindle toxin, toxic when ingested, and was once used as a laxative. It is highly irritating to the skin and mucous membranes, has keratolytic effects, and was used to treat warts and keratosis. It may also possess antitumor properties, as some of its homologues and derivatives also exhibit these properties.
See also: Podophyllum (note moved to).
Indications

For the treatment of genital warts (condyloma acuminata).
Mechanism of Action

Its exact mechanism of action is not fully understood. However, it and its derivatives appear to bind to and inhibit the activity of topoisomerase II in late S phase and early G2 phase. The drug may bind to and stabilize transient breaks caused by this enzyme. This disrupts the repair of breaks in double-stranded DNA, thus preventing DNA unwinding and replication.
The exact mechanism of action of podophyllotoxin is unclear. Podophyllotoxin is a potent cytotoxic agent that inhibits cell mitosis; cell division stops, other cellular processes are impaired, necrosis occurs, and affected tissue is gradually eroded.
Therapeutic Use
Antiviral (Topical)
Podophyllotoxin is indicated for the treatment of genital warts; the gel (not solution) may be used for the treatment of perianal warts. Neither the gel nor the solution should be used to treat warts on mucous membranes, including membranous areas of the urethra, rectum, and vagina. /US product label contains/
Drug Warnings
Due to the possibility of local adverse reactions, the recommended dose, frequency, and duration of treatment with topical podophyllotoxin should not exceed the recommended dose, frequency, and duration. There is no evidence that increasing the frequency of podophyllotoxin use improves efficacy; however, more frequent use is expected to increase the risk of local adverse reactions and increase systemic absorption of the drug. Pregnancy Risk Grade: C / Risk cannot be ruled out. Currently, adequate, well-controlled human studies are lacking, and animal studies have not shown any risk to the fetus or lack relevant data. Use of this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. Topical podophyllotoxin is generally well tolerated. In clinical studies evaluating topical podophyllotoxin for the treatment of external genital and/or perianal warts caused by human papillomavirus in healthy adults aged 18 years and older, up to 6% of patients discontinued treatment due to local adverse reactions; however, no serious systemic adverse reactions have been reported to date. Local adverse reactions, including burning, pain, inflammation, erosion, and itching, typically occur at the application site of 0.5% podophyllotoxin gel or 0.5% solution. These reactions are usually mild to moderate; however, serious local reactions have been reported, especially during the first 2 weeks of treatment. Local adverse reactions typically subside within 4 weeks of completion of topical podophyllotoxin treatment. For more complete data on drug warnings for podophyllotoxin (PODOFILOX, 9 in total), please visit the HSDB record page.

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Pharmacodynamics
Podophyllotoxin, also known as podophyllotoxin, is a purer, more stable form of podophyllotoxin resin containing only the biologically active portion of the compound. Podophyllotoxin is used to remove certain types of warts on the external skin of the genital area.

C22H22O8

414.41188

414.131

518-28-5

Podofilox-d6

10607

White to off-white solid powder

1.4±0.1 g/cm3

597.9±50.0 °C at 760 mmHg

183-184 °C(lit.)

210.2±23.6 °C

0.0±1.8 mmHg at 25°C

1.606

1.6

1

8

4

30

629

4

COC1=CC(=CC(=C1OC)OC)[C@H]2[C@@H]3[C@H](COC3=O)[C@H](C4=CC5=C(C=C24)OCO5)O

YJGVMLPVUAXIQN-XVVDYKMHSA-N

InChI=1S/C22H22O8/c1-25-16-4-10(5-17(26-2)21(16)27-3)18-11-6-14-15(30-9-29-14)7-12(11)20(23)13-8-28-22(24)19(13)18/h4-7,13,18-20,23H,8-9H2,1-3H3/t13-,18+,19-,20-/m0/s1

(5R,5aR,8aR,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~100 mg/mL (~241.31 mM)

Solubility in Formulation 1: ≥ 1.25 mg/mL (3.02 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 12.5 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: ≥ 1.25 mg/mL (3.02 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 12.5 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: ≥ 1.25 mg/mL (3.02 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 12.5 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.)