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
Added (14)C-labeled palmitate was more significantly incorporated into lipid fractions of muscle fibers from fetal and neonatal monkeys than those from adults. /Palmitate/
More (14)C-labeled palmitate was incorporated into lipid by adipose tissue of genetically obese rats than by controls. /Palmitate/
Radioactivity has been traced to the heart, liver, lung, spleen, kidney, muscle, intestine, adrenal, blood, and lymph, and adipose, mucosal, and dental tissues after administration of radioactive oleic, palmitic, or stearic acids.
Fatty acids originating from adipose tissue stores are either bound to serum albumin or remain unesterified in the blood.
For more Absorption, Distribution and Excretion (Complete) data for Palmitic acid (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Palmitic acid is rapidly metabolized, primarily by beta-oxidation. In addition to oxidative breakdown, palmitic acid undergoes a variety of conversion reactions in the liver and intestinal mucosa to stearic, oleic, palmitoleic, and myristic acids. omega-Oxidation, prior to beta-oxidation, may account for 5 to 10% of the hepatic metabolism of palmitic acid in the starved rat. After oxidation or conversion to other long-chain fatty acids or phospholipids, the carbon skeleton of palmitic acid is stored in the form of esterified cholesterol or returned to the plasma, depending upon the nutritional state of the organism.
Proposed mechanisms for fatty acid uptake by different tissues range from passive diffusion to facilitated diffusion or a combination of both. Fatty acids taken up by the tissues can either be stored in the form of triglycerides (98% of which occurs in adipose tissue depots) or they can be oxidized for energy via the beta-oxidation and tricarboxylic acid cycle pathways of catabolism. /Fatty acids/
The beta-oxidation of fatty acids occurs in most vertebrate tissues (except the brain) using an enzyme complex for the series of oxidation and hydration reactions resulting in the cleavage of acetate groups as acetyl-CoA (coenzyme A). An additional isomerization reaction is required for the complete catabolism of oleic acid. Alternate oxidation pathways can be found in the liver (omega-oxidation) and in the brain (alpha-oxidation). /fatty acids/
Fatty acid biosynthesis from acetyl-CoA takes place primarily in the liver, adipose tissue, and mammary glands of higher animals. Successive reduction and dehydration reactions yield saturated fatty acids up to a 16-carbon chain length. /Fatty acids/
Palmitic acid has known human metabolites that include 15-Hydroxy-hexadecanoic acid.

Toxicity Summary
IDENTIFICATION AND USE: Palmitic acid is a solid. It is one of the most common fatty acids, which occurs in natural fats and oils. It is used as soap and cosmetics agent. It is also used in manufacture of metallic palmitates, lube oils, waterproofing, and food-grade additives. HUMAN STUDIES: Palmitic acid was a mild irritant when applied to human skin (75 mg total over 3 days). The excess of saturated free fatty acids, such as palmitic acid, that induces lipotoxicity in hepatocytes, has been implicated in the development of non-alcoholic fatty liver disease also associated with insulin resistance. Growing evidence suggests that the elevation of free fatty acids, including palmitic acid, are associated with inflammation and oxidative stress, which may be involved in endothelial dysfunction, characterized by the reduced bioavailability of nitric oxide (NO) synthesized from endothelial NO synthase (eNOS). Palmitic acid was found to induce significantly elevated levels of biologically active neutrophil chemoattractant, IL-8, from steatotic hepatocytes. In human Chang liver cells palmitic acid induced apoptosis accompanied by autophagy through mitochondrial dysfunction and endoplasmic reticulum stress, which are triggered by oxidative stress. Palmitic acid also stimulated pro-inflammatory responses in human immune cells via Toll-like receptor 4 (TLR4). In large prospective cohort, circulating palmitic acid was associated with higher diabetes risk. However, palmitic acid also plays an important role in early human development. At birth, the term infant is 13-15% body fat, with 45-50% of that as palmitic acid, much of which is derived from endogenous synthesis in the fetus. Palmitic acid is required for biosynthesis of lung lecithin, which is related to fetal maturation. Radiochromatogram showed high incorporation of palmitate into lecithin by fetal lung. Palmitic acid at concentrations up to 100 mg/dL showed little or no toxicity to sperm cells. Palmitic acid markedly suppressed the granulosa cell survival in a time- and dose-dependent manner. ANIMAL STUDIES: Administration of product formulations containing 2.2-74% palmitic acid produced minimal erythema and no edema 2-24 hr after application to the skin of albino rabbits. Administration of commercial grade palmitic acid to the eyes of 6 albino rabbits produced no irritation. Mild to moderate ocular irritation was produced in rabbits by product formulations containing 19.4% palmitic acid. One of these formulations had been diluted to 75% with corn oil. Cosmetic product formulations containing 2.2 and 4.4% palmitic acid produced no ocular irritation in 6 albino rabbits. Administration of up to 10 mL/kg of commercial-grade palmitic acid to rats caused no deaths and no significant gross lesions at necropsy. Transient clinical signs, such as unkempt fur, diarrhea, and slight CNS depression were seen at 4.64 and 10 mL/kg. Rats fed diets containing 4.6 g/kg/day palmitic acid for 6 weeks developed hyperlipemia. Rats that ingested a diet containing 6% palmitic acid for 16 weeks developed atherosclerotic lesions. Palmitic acid was administered to 16 mice at a dose of 1.0 mg 3 times per week for a total of 10 injections (total dose, 10 mg palmitic acid/mL tricaprylin). Eight mice were alive after 12 months, and 6 were alive after 18 months. One subcutaneous sarcoma was found after 19 months, 2 pulmonary neoplasms were found after 19 and 22 months, and 1 breast carcinoma was found after 22 months. Brief palmitic acid exposure of murine blastocysts resulted in altered embryonic metabolism and growth, with lasting adverse effects on offspring. Palmitic acid inhibited the cell growth in rat hepatocytes.

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Interactions
Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients.
Non-alcoholic steatohepatitis (NASH) is an increasingly common cause of chronic liver disease; however, no specific pharmacologic therapy has been shown to be effective in its treatment. The present study was designed to develop an experimental cell culture model of NASH using four kinds of fatty acids - palmitic acid (PA), stearic acid (SA), linoleic acid (LA), and oleic acid (OA) - and TNF-a, according to the two-hit hypothesis. The saturated fatty acids PA and SA are more cytotoxic than the unsaturated fatty acids OA and LA. Cellular lipid accumulation without cytotoxicity was more easily induced with the unsaturated fatty acids than with the saturated fatty acids. PA augmented TNF-a-induced cytotoxicity, while the unsaturated fatty acids attenuated TNF-a-induced cytotoxicity. In a mechanistic study, PA enhanced TNF-a-mediated apoptosis in the absence of oxidative stress, as determined by measuring the cellular glutathione and malondialdehyde levels. Moreover, PA inhibited the TNF-a-induced phosphorylation of AKT, but not c-Jun N-terminal kinase, indicating that inhibition of survival signaling pathways activated by TNF-a may explain the effects of PA on TNF-a-induced cytotoxicity. The in vitro NASH model established in this study may be used to screen drug candidates for suitability for the treatment of NASH.
/The study objective was/ to observe the effects of total flavonoids of tartary buckwheat on NO synthesis in EA.hy926 cells induced by palmitic acid. EA.hy926 cells were cultured in vitro and randomly divided into control group, palmitic acid-induced insulin resistance group, total flavonoids of tartary buckwheat group and metformin group. The content of NO in supernatant was detected by nitrate reductase. The eNOS mRNA and protein expression levels were determined by RT-PCR and Western blotting, respectively. Compared with control group, the NO content in supernatant and the expression levels of eNOS mRNA and protein were significantly lower in insulin resistance group (P<0.05). Compared with insulin resistance group, the NO content in supernatant, as well as the eNOS mRNA and protein expression markedly increased in both total flavonoids of tartary buckwheat group and metformin group (P<0.05), but there was no significant difference between the latter two groups (P>0.05). Total flavonoids of tartary buckwheat effectively promotes the expression of eNOS mRNA and protein in endothelial cells under palmitic acid stimulation, thereby contributing to the NO synthesis.
The excess of saturated free fatty acids, such as palmitic acid, that induces lipotoxicity in hepatocytes, has been implicated in the development of non-alcoholic fatty liver disease also associated with insulin resistance. By contrast, oleic acid, a monounsaturated fatty acid, attenuates the effects of palmitic acid. We evaluated whether palmitic acid is directly associated with both insulin resistance and lipoapoptosis in mouse and human hepatocytes and the impact of oleic acid in the molecular mechanisms that mediate both processes. In human and mouse hepatocytes palmitic acid at a lipotoxic concentration triggered early activation of endoplasmic reticulum (ER) stress-related kinases, induced the apoptotic transcription factor CHOP, activated caspase 3 and increased the percentage of apoptotic cells. These effects concurred with decreased IR/IRS1/Akt insulin pathway. Oleic acid suppressed the toxic effects of palmitic acid on ER stress activation, lipoapoptosis and insulin resistance. Besides, oleic acid suppressed palmitic acid-induced activation of S6K1. This protection was mimicked by pharmacological or genetic inhibition of S6K1 in hepatocytes. ...
For more Interactions (Complete) data for Palmitic acid (22 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse iv 57 mg/kg

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

[2]. Antitumor activity of palmitic acid found as a selective cytotoxic substance in a marine red alga. Anticancer Res. 2002 Sep-Oct;22(5):2587-90.

Hexadecanoic acid is a straight-chain, sixteen-carbon, saturated long-chain fatty acid. It has a role as an EC 1.1.1.189 (prostaglandin-E2 9-reductase) inhibitor, a plant metabolite, a Daphnia magna metabolite and an algal metabolite. It is a long-chain fatty acid and a straight-chain saturated fatty acid. It is a conjugate acid of a hexadecanoate.
A common saturated fatty acid found in fats and waxes including olive oil, palm oil, and body lipids.
Palmitic acid is a metabolite found in or produced by Escherichia coli (strain K12, MG1655).
Palmitic Acid has been reported in Calodendrum capense, Camellia sinensis, and other organisms with data available.
Palmitic Acid is a saturated long-chain fatty acid with a 16-carbon backbone. Palmitic acid is found naturally in palm oil and palm kernel oil, as well as in butter, cheese, milk and meat.
Palmitic acid, or hexadecanoic acid is one of the most common saturated fatty acids found in animals and plants, a saturated fatty acid found in fats and waxes including olive oil, palm oil, and body lipids. It occurs in the form of esters (glycerides) in oils and fats of vegetable and animal origin and is usually obtained from palm oil, which is widely distributed in plants. Palmitic acid is used in determination of water hardness and is an active ingredient of *Levovist*TM, used in echo enhancement in sonographic Doppler B-mode imaging and as an ultrasound contrast medium.
A common saturated fatty acid found in fats and waxes including olive oil, palm oil, and body lipids.
See also: Fatty acids, C14-18 (annotation moved to).

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Mechanism of Action
... Excessive palmitoylcarnitine formation and exhausted L-carnitine stores leading to energy depletion, attenuated acetylcholine synthesis and oxidative stress to be main mechanisms behind PA-induced neuronal loss.High PA exposure is suggested to be a factor in causing diabetic neuropathy and gastrointestinal dysregulation.
... First phase insulin release response was lost in these islets. FFAs slightly increased the insulin output of normal fresh pancreas beta-cells. However, chronic exposure to FFAs resulted in loss of first phase insulin release and blunted insulin secretion response to various levels of D-glucose stimulation.

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Therapeutic Uses
/EXPL THER/ Recent studies indicate that lipid metabolic changes affect the survival of multiple myeloma (MM) cells. Time-of-flight secondary ion mass spectrometry (TOF-SIMS), an imaging mass spectrometry technique, is used to visualize the subcellular distribution of biomolecules including lipids. We therefore applied this method to human clinical specimens to analyze the membrane fatty acid composition and determine candidate molecules for MM therapies. We isolated MM cells and normal plasma cells (PCs) from bone marrow aspirates of MM patients and healthy volunteers, respectively, and these separated cells were analyzed by TOF-SIMS. Multiple ions including fatty acids were detected and their ion counts were estimated. In MM cells, the mean intensity of palmitic acid was significantly lower than the mean intensity in PCs. In a cell death assay, palmitic acid reduced U266 cell viability dose-dependently at doses between 50 and 1000 uM. The percentage of apoptotic cells increased from 24 hr after palmitic acid administration. In contrast, palmitic acid had no effect on the viability of normal peripheral blood mononuclear cells (PBMCs). The results of this study indicated that palmitic acid is a potential candidate for novel therapeutic agents that specifically attack MM cells.
/EXPL THER/ Approximately 80% of all new HIV-1 infections are acquired through sexual contact. Currently, there is no clinically approved microbicide, indicating a clear and urgent therapeutic need. We recently reported that palmitic acid (PA) is a novel and specific inhibitor of HIV-1 fusion and entry. Mechanistically, PA inhibits HIV-1 infection by binding to a novel pocket on the CD4 receptor and blocks efficient gp120-to-CD4 attachment. Here, we wanted to assess the ability of PA to inhibit HIV-1 infection in cervical tissue ex vivo model of human vagina, and determine its effect on Lactobacillus (L) species of probiotic vaginal flora. Our results show that treatment with 100-200 uM PA inhibited HIV-1 infection in cervical tissue by up to 50%, and this treatment was not toxic to the tissue or to L. crispatus and jensenii species of vaginal flora. In vitro, in a cell free system that is independent of in vivo cell associated CD4 receptor; we determined inhibition constant (Ki) to be ~2.53 uM. These results demonstrate utility of PA as a model molecule for further preclinical development of a safe and potent HIV-1 entry microbicide inhibitor.
/EXPL THER/ In a recent laboratory study, a fatty acid from seaweed reduced the ability of HIV-1 viruses to enter immune system cells. The study was reported in the journal AIDS Research and Human Retroviruses. Drug-resistant strains of HIV-1 have been on the rise, prompting the need for new therapeutic agents. Previous studies have demonstrated that products derived from natural sources have the potential to inhibit HIV-1 infection. In this laboratory study, researchers evaluated palmitic acid (from Sargassum fusiforme, a type of seaweed that grows off the coasts of Japan and China) to see if palmitic acid reduced the ability of HIV-1 viruses to enter CD4+ T-cells (white blood cells that are HIV-1's main target). Palmitic acid blocked both X4-tropic and R5-tropic viruses, the HIV viruses that use a particular receptor (X4 or R5) to enter a cell. In addition, the study's findings showed that palmitic acid protected other cells against HIV-1, reducing X4 infection in primary peripheral blood lymphocytes and R5 infection in primary macrophages (white blood cells). In all cases, the extent of the blocking effect depended on the concentration of palmitic acid, and most cells remained viable (alive) after treatment. The researchers noted that understanding the relationship between palmitic acid and CD4 may lead to development of an effective microbicide product for preventing sexual transmission of HIV.
/EXPL THER/ The high rate of HIV-1 mutation and the frequent sexual transmission highlight the need for novel therapeutic modalities with broad activity against both CXCR4 (X4) and CCR5 (R5)-tropic viruses. We investigated a large number of natural products, and from Sargassum fusiforme we isolated and identified palmitic acid (PA) as a natural small bioactive molecule with activity against HIV-1 infection. Treatment with 100 uM PA inhibited both X4 and R5 independent infection in the T cell line up to 70%. Treatment with 22 uM PA inhibited X4 infection in primary peripheral blood lymphocytes (PBL) up to 95% and 100 uM PA inhibited R5 infection in primary macrophages by over 90%. Inhibition of infection was concentration dependent, and cell viability for all treatments tested remained above 80%, similar to treatment with 10(-6)M nucleoside analogue 2',3'-dideoxycytidine (ddC). Micromolar PA concentrations also inhibited cell-to-cell fusion and specific virus-to-cell fusion up to 62%. PA treatment did not result in internalization of the cell surface CD4 receptor or lipid raft disruption, and it did not inhibit intracellular virus replication. PA directly inhibited gp120-CD4 complex formation in a dose-dependent manner. We used fluorescence spectroscopy to determine that PA binds to the CD4 receptor with K(d) approximately 1.5 +/- 0.2 uM, and we used one-dimensional saturation transfer difference NMR (STD-NMR) to determined that the PA binding epitope for CD4 consists of the hydrophobic methyl and methelene groups located away from the PA carboxyl terminal, which blocks efficient gp120-CD4 attachment. These findings introduce a novel class of antiviral compound that binds directly to the CD4 receptor, blocking HIV-1 entry and infection. Understanding the structure-affinity relationship (SAR) between PA and CD4 should lead to the development of PA analogs with greater potency against HIV-1 entry.

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Pharmacodynamics
Palmitic acid is the first fatty acid produced during lipogenesis (fatty acid synthesis) and from which longer fatty acids can be produced. Palmitate negatively feeds back on acetyl-CoA carboxylase (ACC) which is responsible for converting acetyl-ACP to malonyl-ACP on the growing acyl chain, thus preventing further palmitate generation

C16H32O2

256.424085617065

256.24

1219802-61-5

Palmitic acid;57-10-3

985

White crystalline scales
White crystalline needles
Needles from alcohol
Hard, white, or faintly yellowish, somewhat glossy crystalline solid, or as a white yellowish powder

0.9±0.1 g/cm3

340.6±5.0 °C at 760 mmHg

154.1±12.5 °C

0.0±0.8 mmHg at 25°C

1.454

7.15

1

2

14

18

178

0

C(CCCC([H])([H])C(=O)O)CCCCCCCCCC([H])([H])[H]

IPCSVZSSVZVIGE-UHFFFAOYSA-N

InChI=1S/C16H32O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16(17)18/h2-15H2,1H3,(H,17,18)

hexadecanoic acid

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.)