Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

Absorption, Distribution and Excretion
Oral Administration: After oral administration, capsaicin is absorbed from the stomach and whole intestine via an inactive process, with absorption rates varying from 50% to 90% depending on the animal. Peak plasma concentrations are reached within 1 hour after administration. After absorption from the stomach into the small intestine, capsaicin may undergo minor metabolism in the small intestinal epithelial cells. Although human oral pharmacokinetic information is limited, capsaicin is detectable in plasma within 10 minutes after ingestion of an equivalent dose of 26.6 mg of pure capsaicin, reaching a peak plasma concentration of 2.47 ± 0.13 ng/ml at 47.1 ± 2.0 minutes. Systemic Absorption: Following intravenous or subcutaneous injection in animals, drug concentrations in the brain and spinal cord are approximately 5 times higher than in the blood, and drug concentrations in the liver are approximately 3 times higher than in the blood. Topical Administration: Capsaicin is rapidly and adequately absorbed through human skin, but systemic absorption is unlikely after local or transdermal administration. A population analysis was conducted on patients using a topical patch containing 179 mg capsaicin, and plasma capsaicin concentrations were fitted using a one-compartment model of first-order absorption and linear elimination. The mean peak plasma concentration was 1.86 ng/mL, but the highest observed concentration in any patient was 17.8 ng/mL. It is presumed that capsaicin is primarily excreted by the kidneys in its original form and as a glucuronide. Small amounts of the original compound are excreted in feces and urine. In vivo animal studies showed that less than 10% of the administered dose was detected on the face after 48 hours. Prescription and over-the-counter medications for local analgesia, including creams, lotions, and patches, contain capsaicin (CAP) and dihydrocapsaicin (DHC). Currently, there are limited in vivo studies on the absorption, bioavailability, and distribution of CAP and DHC. We developed a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the levels of CAP and DHC in rabbit plasma and tissues. Biological samples were prepared by liquid-liquid extraction using a hexane-dichloromethane-isopropanol mixture (100:50:5, v/v/v), followed by isocratic chromatography using an Extend C18 column. The mobile phase was acetonitrile-water-formic acid (70:30:0.1, v/v/v). For 100 μL of biological samples, the method was linear in the range of 0.125 to 50 ng/mL, with a limit of quantitation of 0.125 ng/mL. The total run time for analyzing each sample was 3.5 minutes. We used this validation method to investigate the pharmacokinetics and tissue distribution of topically applied capsaicin gel (CAP gel) in rabbits. Very small amounts of capsaicin and dihydrocapsaicin were absorbed into systemic circulation. The highest plasma concentration was 2.39 ng/mL, with a mean peak plasma concentration of 1.68 ng/mL 12 hours after CAP gel application. Drug concentrations were relatively high in the treated skin, but lower in other tissues. Therefore, topical application of capsaicin gel has strong local effects and weak systemic effects.

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Metabolism/Metabolites
The metabolic pathway of orally administered capsaicin is not yet clear, but it is expected to be primarily metabolized in the liver, with minimal metabolism in the intestinal lumen.In vitro studies have shown that capsaicin is rapidly metabolized in human liver microsomes and the S9 fragment, mainly producing three metabolites: 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, while vanillin is a minor metabolite. Studies speculate that cytochrome P450 (P450) enzymes may play a role in hepatic drug metabolism. In vitro studies have shown that the biotransformation of capsaicin in human skin is slow, with most capsaicin remaining unchanged. Capsaicin and dihydrocapsaicin are the main active ingredients in pepper spray, which is widely used for law enforcement and self-defense. Due to the irreversible health hazards of pepper spray, its use has been highly controversial. This study compared the metabolism and cytotoxicity of capsaicin and dihydrocapsaicin in vitro using human hepatocytes, porcine hepatocyte fractions, and the human lung cancer cell line (A549). Metabolites were screened and identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A novel dihydrocapsaicin aliphatic hydroxylated metabolite (m/z 322) was detected in hepatocyte fractions, but no structure corresponding to capsaicin was found. Conversely, a novel capsaicin phase I metabolite was identified, with a structure corresponding to aliphatic demethylation and dehydrogenation (m/z 294). Furthermore, two novel conjugates of capsaicin and dihydrocapsaicin were identified: glycine conjugates (m/z 363 and m/z 365) and diglutathione (GSH) conjugates (m/z 902 and m/z 904). A549 cell culture medium exposed to capsaicin contained capsaicin in ω-hydroxylated (m/z 322) and alkyl dehydrogenated (m/z 304) forms, as well as a glycine conjugate. For dihydrocapsaicin, an alkyl dehydrogenated form (m/z 306), a novel alkyl hydroxylated form, and a novel glycine conjugate were discovered. In A549 cells, dihydrocapsaicin induced cell vacuolation and reduced cell viability more effectively than capsaicin. Furthermore, both compounds induced p53 protein expression and G1 phase cell cycle arrest. The applicability of these metabolites as biomarkers for capsaicin exposure requires further investigation using other toxicity endpoints. ...Dehydrogenation of capsaicin is a novel metabolic pathway, producing unique cyclic, diene, and imide metabolites. 1-Aminobenzotriazole (1-ABT) inhibits the metabolism of capsaicin in microsomes. CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 catalyze the metabolism of capsaicin. Adding GSH (2 mM) to the microsomal incubation medium stimulates capsaicin metabolism and captures various active electrophilic intermediates, causing them to form adducts with GSH. /This study used recombinant P450 enzymes and liver and lung microsomes from multiple species, including humans./
This study aimed to characterize capsaicin glucuronidation using liver microsomes and determine the roles of various UDP-glucuronyltransferases (UGTs) in hepatic capsaicin glucuronidation. The glucuronidation rate was determined by incubating capsaicin with microsomes supplemented with uridine diphosphate glucuronide. Kinetic parameters were obtained through model fitting. Relative activity factors, expression-activity correlations, and activity correlations were determined to identify the major UGT enzymes involved in capsaicin metabolism. Capsaicin is efficiently glucuronidated in mixed human liver microsomes (pHLM). UGT1A1, 1A9, and 2B7 (as well as gastrointestinal enzymes UGT1A7 and 1A8) all exhibited relatively high activities. In a sample library containing liver microsomes from 14 individuals, capsaicin glucuronidation was significantly correlated with β-estradiol 3-O-glucuronidation (r=0.637; p=0.014) and UGT1A1 protein levels (r=0.616; p=0.019). Furthermore, capsaicin glucuronidation was significantly positively correlated with zidovudine glucuronidation (r=0.765; p<0.01) and UGT2B7 protein levels (r=0.721; p<0.01). In human liver microsomes (pHLM), UGT1A1, 1A9, and 2B7 contributed 30.3%, 6.0%, and 49.0% of total capsaicin glucuronidation, respectively. Moreover, the effect of liver microsomes on capsaicin glucuronidation showed significant species differences.

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Biological Half-Life
After oral administration of an equivalent dose of 26.6 mg of pure capsaicin, the half-life is approximately 24.9 ± 5.0 min. After topical application of a 3% capsaicin solution, the half-life of capsaicin is approximately 24 h.After using a topical patch containing 179 mg of capsaicin, the mean population elimination half-life is 1.64 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the clinical application of topical capsaicin during lactation. However, topical capsaicin has a low absorption rate, making it unlikely to enter the infant's bloodstream and therefore unlikely to cause any adverse effects on breastfed infants. Avoid applying to the nipple area and ensure that the infant's skin does not come into direct contact with any areas where capsaicin has been applied.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Breastfeeding and Breast Milk
No published information found as of the revision date.
◈ What is Capsaicin?
Capsaicin is the component in chili peppers (Capsicum genus of the Solanaceae family) that produces the pungent sensation in the mouth. Capsaicin has been designated as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration (FDA) and can be used in food and confectionery. It is also used in some cosmetics and is a key ingredient in pepper spray for self-defense. Topical capsaicin preparations (applied to the skin) are used to treat pain and have also been injected into the foot to help treat pain caused by Morton's neuroma (a foot nerve disorder). Some brand names for topical preparations include Capazasin®, Qutenza®, and Zostrix®. Capsaicin has also been sold as an herbal supplement in oral dosage forms such as tablets and capsules. Herbal products are generally not recommended for use during pregnancy unless used to treat a medical condition under the guidance and care of a healthcare provider. For more information on herbal products, please see our fact sheet: https://mothertobaby.org/fact-sheets/herbal-products-pregnancy/.
◈ I take capsaicin. Will taking capsaicin affect my pregnancy?
There are currently no human studies to confirm that taking capsaicin affects pregnancy. Animal studies have also not found that capsaicin affects female fertility.
◈ Does taking capsaicin increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There are currently no studies to confirm that capsaicin increases the risk of miscarriage.
◈ Does taking capsaicin increase the risk of birth defects?
There is a 3-5% risk of birth defects in each pregnancy, known as the baseline risk. Currently, no human studies have confirmed that capsaicin increases the risk of birth defects above the baseline risk. Animal studies have shown that capsaicin does not increase the risk of birth defects.
◈ Does taking capsaicin during pregnancy increase the risk of other pregnancy-related problems?
Currently, no human studies have confirmed whether capsaicin causes other pregnancy-related problems, such as premature birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). One animal study suggests that capsaicin may affect fetal growth and development.
◈ Will taking capsaicin during pregnancy affect a child's future behavior or learning abilities?
Currently, no studies have confirmed whether capsaicin causes behavioral or learning problems in children.
◈ Taking capsaicin while breastfeeding:
Currently, no studies have confirmed the effects of capsaicin on breastfeeding women. Two breastfed infants reported developing rashes 12 and 15 hours after their mothers consumed foods seasoned with red chili peppers. The infants' skin reactions subsided within a few days. If you suspect your infant has any symptoms, such as a rash, contact your child's healthcare provider. Be sure to discuss all your breastfeeding questions with your healthcare provider.
◈ Does capsaicin intake by men affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
Currently, no human studies have determined whether capsaicin affects male fertility or increases the risk of birth defects (above background risk). Animal studies have also not shown that capsaicin affects male fertility. Generally, exposure to capsaicin by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please refer to MotherToBaby's "Father Exposure" fact sheet at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019;53(2):211-216.

[2]. Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1). Br J Pharmacol. 2005 Mar;144(6):781-90.

[3]. The Effect of Capsaicin on Salivary Gland Dysfunction. Molecules. 2016 Jun 25;21(7).

[4]. Capsaicin provokes apoptosis and restricts benzo(a)pyrene induced lung tumorigenesis in Swiss albino mice. Int Immunopharmacol. 2013 Jun 6;17(2):254-259.

Capsaicin is a capsaicinoid compound. It has non-anesthetic analgesic, voltage-gated sodium channel blocker, and TRPV1 agonist effects. Capsaicin is most commonly used for local analgesia and is available in various concentrations of creams, liquids, and patches; it may also be found in some dietary supplements. Capsaicin is a naturally occurring plant stimulant found in chili peppers and can also be synthesized for use in pharmaceutical preparations. The U.S. Food and Drug Administration (FDA) recently approved Qutenza, an 8% capsaicin patch for the treatment of neuropathic pain, including postherpetic neuralgia. Capsaicin has been reported to be found in chili peppers (Capsicum pubescens), capsicum annuum, and other plants in the Capsicum genus, but relevant data are still unclear. Capsaicin is a chili pepper extract with analgesic properties. Capsaicin is a neuropeptide releaser that selectively acts on peripheral neurons of the primary sensory system. Topical application of capsaicin helps control peripheral nerve pain. This substance has been used experimentally to modulate substance P and other tachykinins. In addition, capsaicin may help control mucositis caused by chemotherapy and radiotherapy. Capsaicin is considered the main pungent component in the fruits of plants in the genus Capsicum. Chili peppers (belonging to the genus Capsicum in the family Solanaceae) are one of the most consumed spices in the world. The capsaicin content in green and red bell peppers ranges from 0.1% to 1%. Capsaicin has a variety of biological effects and has therefore been the subject of extensive research since its first discovery in 1919. One of the most well-known physiological properties of capsaicin is its selective action on the peripheral parts of the sensory nervous system, particularly primary afferent neurons. Capsaicin is known to deplete the neurotransmitter responsible for transmitting pain signals (substance P) in sensory nerve endings; therefore, it is used as a versatile experimental tool for studying pain mechanisms and can also be used to treat certain peripheral pain conditions such as rheumatoid arthritis, postherpetic neuralgia, post-mastectomy pain syndrome, and diabetic neuropathy. Given the widespread use of capsaicin as a food additive and its current therapeutic applications, it is crucial from a public health perspective to properly assess any harmful effects of this compound. It has been reported that high intake of capsaicin can lead to histopathological and biochemical changes, including gastric mucosal erosion and liver necrosis. However, conflicting data exist regarding the mutagenicity of capsaicin. A recent epidemiological study in Mexico indicated that people who eat chili peppers have a higher risk of stomach cancer than those who do not. However, it remains unclear whether capsaicin, present in chili peppers, is a major contributing factor to human stomach cancer. A growing body of recent research focuses on anticancer or antimutagenic phytochemicals, particularly those found in the human diet. In summary, capsaicin has a dual role in both chemically induced carcinogenesis and mutagenesis. While trace amounts of capsaicin have little or no harmful effects, high intake of this compound is associated with necrosis, ulceration, and even cancer. Capsaicin is believed to be metabolized into its active form by cytochrome P-450-dependent mixed-function oxidases. (A7835)
An alkylamide found in chili peppers that acts on TRPV cation channels.
See also: Capsicum oleoresin (active ingredient); Chili pepper (part). Chili powder (partial)...See more...

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Drug Indications
8% capsaicin patches are indicated for the treatment of neuropathic pain associated with postherpetic neuralgia. Various topical capsaicin preparations, including creams and solutions, are available for temporary relief of muscle and joint pain as well as neuropathic pain.
FDA Label
Qutenza is indicated for the treatment of peripheral neuropathic pain in adults, either alone or in combination with other analgesics.

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Mechanism of Action
Studies have shown that capsaicin can reduce the levels of substance P, which is associated with inflammation, but this is not its primary mechanism of pain relief. The mechanism of action of capsaicin is through inducing a local allergic reaction in the skin, causing the nociceptor fibers to "inactivate." This alteration of the pain mechanism is caused by a combination of factors: temporary loss of membrane potential, impaired neurotrophic factor transport leading to phenotypic changes, and reversible retraction of nerve fiber endings in the epidermis and dermis.
Capsaicin is the pungent component of chili peppers and is a typical representative of capsaicinoids or vanillinoids. These compounds can stimulate and subsequently desensitize specific subsets of sensory receptors, including C-type multimodal nociceptors, Aδ-type mechanothermal nociceptors, cutaneous thermoreceptors, and enteroreceptors in fine afferent fibers. … In rats receiving intraperitoneal injection of capsaicin (i.e., non-systemic abdominal desensitization), the primary manifestation was a reduction in the initial rather than later stages of fever. Postprandial hyperthermia induced by intragastric injection of barium sulfate suspension could be attenuated by intraperitoneal or perineurial injection of capsaicin. … Heat, protons, and capsaicin can all activate VR1, inducing cation influx (especially Ca2+ and Na+ ions). The characteristic effects of capsaicin are a burning sensation after acute administration and sensory neuronal desensitization after high-dose and long-term administration. … Capsaicin alters various visceral functions. Injection of capsaicin into the hypothalamus affects thermoregulation and releases glutamate from hypothalamic and cerebral cortical sections, areas where no VR1-like immunoreactivity was observed.
...Capsaicin at 0.4 μM and 4 μM exhibited significant and sustained inhibition of voltage-activated Na+ current (I(Na)), induced by depolarization from a holding potential of -100 mV to -40 mV (49 ± 7%, n=11, p<0.05 and 72 ± 13%, n=4, p<0.05, respectively). ...Capsaicin slowed the decay time of I(Na) inactivation and increased the time constant of inactivation recovery. Capsaicin and tetrodotoxin (TTX) inhibited the contractility of isolated electrically stimulated rat left atrium, as evidenced by a decrease in the rate of maximum force development (dF/dt(max)) relative to the control, with a reduction of 19 ± 3% in the 1 μM capsaicin group and 22 ± 2% in the 1 μM TTX group.
For more data (8 items) on the complete mechanism of action of capsaicin, please visit the HSDB record page.

C18H27NO3

305.411885499954

305.199

1217899-52-9

Capsaicin;404-86-4

1548943

White to off-white solid powder

3.6

2

3

9

22

341

0

c1(OC)cc(CNC(=O)CCCC/C=C/C(C)C)ccc1O

YKPUWZUDDOIDPM-SOFGYWHQSA-N

InChI=1S/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6+

(E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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