Ivermectin (formerly known as MK-933; Noromectin; Mectizan; Ivomec; L-64047; Pandex) is an effective and widely used antiparasitic medication approved for use in human and veterinary medicine against many types of parasites. It has been reported that Ivermectin may be used for COVID-19 treatment, but so far it has not approved by the FDA for the treatment of any viral infection. Ivermectin acts as a positive allosteric effector of P2X4 and the α7 neuronal nicotinic acetylcholine receptor (nAChRs). Ivermectin is used to treat head lice, scabies, river blindness, strongyloidiasis, and lymphatic filariasis, among others. Ivermectin and other avermectins (insecticides most frequently used in home-use ant baits) are macrocyclic lactones derived from the bacterium Streptomyces avermitilis. Ivermectin kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission. Ivermectin is a mixture of mostly avermectin H2B1a with some avermectin H2B1b (CAS# 70209-81-3), which are macrolides from STREPTOMYCES avermitilis.
Physicochemical Properties
| Molecular Formula | C48H74O14 |
| Molecular Weight | 875.1 |
| Exact Mass | 874.508 |
| CAS # | 70288-86-7 |
| PubChem CID | 6321424 |
| Appearance | White to off-white solid powder |
| Melting Point | 155 °C |
| LogP | 5.601 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 14 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 62 |
| Complexity | 1680 |
| Defined Atom Stereocenter Count | 20 |
| SMILES | CC[C@H](C)[C@@H]1[C@H](CC[C@@]2(O1)C[C@@H]3C[C@H](O2)C/C=C(/[C@H]([C@H](/C=C/C=C/4\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O[C@H]7C[C@@H]([C@H]([C@@H](O7)C)O)OC)OC)\C)C |
| InChi Key | AZSNMRSAGSSBNP-ZGXOMDHGSA-N |
| InChi Code | InChI=1S/C48H74O14/c1-11-25(2)43-28(5)17-18-47(62-43)23-34-20-33(61-47)16-15-27(4)42(26(3)13-12-14-32-24-55-45-40(49)29(6)19-35(46(51)58-34)48(32,45)52)59-39-22-37(54-10)44(31(8)57-39)60-38-21-36(53-9)41(50)30(7)56-38/h12-15,19,25-26,28,30-31,33-45,49-50,52H,11,16-18,20-24H2,1-10H3/b13-12+,27-15+,32-14+/t25-,26+,28+,30+,31+,33-,34+,35+,36+,37+,38+,39+,40-,41+,42+,43-,44+,45-,47-,48-/m1/s1 |
| Chemical Name | (1R,4S,5'S,6R,6'R,8R,10E,12S,13S,14E,16E,20R,21R,24S)-6'-[(2R)-butan-2-yl]-21,24-dihydroxy-12-[(2R,4S,5S,6S)-5-[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-5',11,13,22-tetramethylspiro[3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one |
| Synonyms | MK-933; L-64047; MK 933; L64047; MK-0933; Noromectin; MK 933; Mectizan; MK 0933; Ivermectin; Ivomec; L 64047; Pandex. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | HIV-1; HSV-1; BoHV-1; SARS-CoV-2; |
| ln Vitro |
Ivermectin (MK-933) acts quickly and reversibly in the submicromolar range (EC50=250 nM), increasing the amplitude and delaying the deactivation of ATP-evoked P2X4 channel currents.Without altering the ion selectivity of P2X4 channels, ivermectin (MK-933) significantly boosts the potency of ATP and that of the typically low-potency agonist a,b-methylene-ATP in a use- and voltage-independent manner[1]. Ivermectin (MK-933) causes membrane hyperpolarization and muscular paralysis in the parasite by activating glutamate-gated chloride channels in its nerves and muscles[2]. The binding of Impα/β1 to NS5 is strongly inhibited by ivermectin (MK-933) (IC50=17 μM), but not the binding of Impβ1 by itself.Ivermectin (MK-933) exhibits strong antiviral activity against the dengue virus and HIV-1, which are both heavily dependent on importin α/β nuclear import with regard to the NS5 (non-structural protein 5) polymerase and HIV-1 integrase proteins, respectively[3]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Moderately well absorbed. Improved absorption with high fat meal. Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. The volume of distribution is 3 to 3.5 L/kg and it does not cross the blood-brain barrier. Metabolism / Metabolites Primarily hepatic. Ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1 % of the administered dose excreted in the urine. Biological Half-Life Following oral administration, the half-life of ivermectin is approximately 18 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Single dose therapy with ivermectin has been associated with a low rate of serum aminotransferase elevations. A single case of clinically apparent liver injury has been reported after ivermectin use (Case 1). The onset of injury occurred 1 month after a single dose and was characterized by a hepatocellular pattern of serum enzyme elevations without jaundice. Recovery was rapid and complete. In trials of ivermectin to prevent SARS-CoV-2 infection and to ameliorate the course of early as well as severe COVID-19, serum aminotransferase elevations were not uncommon but were no more frequent among patients receiving ivermectin than among those receiving placebo or a comparator drug. Likelihood score: D (possible rare cause of mild clinically apparent liver injury). Protein Binding 93% |
| References |
[1]. Allosteric control of gating and kinetics at P2X(4) receptor channels. J Neurosci. 1999 Sep 1;19(17):7289-99. [2]. Mechanism of ivermectin facilitation of human P2X4 receptor channels. J Gen Physiol. 2004 Mar;123(3):281-93. [3]. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012 May 1;443(3):851-6. [4]. Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes with Viral Replication. Microorganisms. 2020 Mar 13;8(3). pii: E409. [5]. Ivermectin, a New Candidate Therapeutic Against SARS-CoV-2/COVID-19. Ann Clin Microbiol Antimicrob. 2020 May 30;19(1):23. |
| Additional Infomation |
LSM-5397 is a milbemycin. Ivermectin is a semi-synthetic antiparasitic medication derived from avermectins, a class of highly-active broad-spectrum antiparasitic agents isolated from the fermentation products of Streptomyces avermitilis. Ivermectin itself is a mixture of two avermectins, comprising roughly 90% 5-O-demethyl-22,23-dihydroavermectin A1a (22,23-dihydroavermectin B1a) and 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a (22,23-dihydroavermectin B1b). Ivermectin is mainly used in humans in the treatment of onchocerciasis, but may also be effective against other worm infestations (such as strongyloidiasis, ascariasis, trichuriasis and enterobiasis). Applied topically, it may be used in the treatment of head lice infestation. With the advent of 2020 and the COVID-19 pandemic, ivermectin began garnering notoriety due to its off-label use for the prophylaxis and treatment of COVID-19. While studies are still ongoing, much of the evidence for ivermectin in COVID-19 relies on pre-print in vitro data, and the clinical utility of this data remains unclear. Due to a number of factors - for example, the relatively low number of patients per trial and the speed at which these trials were conducted - studies on the use of ivermectin in COVID-19 have been fraught with statistical errors and accusations of plagiarism. In addition, the use of aggregate patient data in large-scale meta-analyses (as opposed to individual patient data (IPD)) has been shown to disguise otherwise blatant data errors, such as extreme terminal digit bias and the duplication of blocks of patient records. Until high-quality, peer-reviewed data regarding both the safety and efficacy of ivermectin for COVID-19 in humans becomes available, the use of ivermectin for these purposes should be avoided in favour of thoroughly-vetted therapies (e.g. COVID-19 vaccines like [Comirnaty](https://go.drugbank.com/drugs/DB15696)). Ivermectin is an antiinfective agent with activity against several parasitic nematodes and scabies and is the treatment of choice for onchocerciasis (river blindness). It is typically given as one or two oral doses. Ivermectin therapy has been associated with minor, self-limiting serum aminotransferase elevations and very rare instances of clinically apparent liver injury. Ivermectin B1a has been reported in Streptomyces avermitilis with data available. Ivermectin is an orally bioavailable macrocyclic lactone derived from Streptomyces avermitilis, with antiparasitic and potential anti-viral activities. Upon administration, ivermectin exerts its anthelmintic effect through binding and activating glutamate-gated chloride channels (GluCls) expressed on nematode neurons and pharyngeal muscle cells. This causes increased permeability of chloride ions, causing a state of hyperpolarization and results in the paralysis and death of the parasite. Ivermectin may exerts its antiviral effect, including its potential activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), by binding to the importin (IMP) alpha/beta1 heterodimer, which is responsible for the nuclear import of viral proteins such as the integrase (IN) protein. This inhibits nuclear import of host and viral proteins and may inhibit viral replication. A mixture of mostly avermectin H2B1a (RN 71827-03-7) with some avermectin H2B1b (RN 70209-81-3), which are macrolides from STREPTOMYCES avermitilis. It binds glutamate-gated chloride channel to cause increased permeability and hyperpolarization of nerve and muscle cells. It also interacts with other CHLORIDE CHANNELS. It is a broad spectrum antiparasitic that is active against microfilariae of ONCHOCERCA VOLVULUS but not the adult form. See also: Ivermectin (annotation moved to). Drug Indication Administered topically, ivermectin cream is indicated for the treatment of inflammatory lesions associated with rosacea. An over-the-counter ivermection lotion is commercially available and indicated for the topical treatment of head lice infestations in patients ≥6 months of age. Orally administered ivermectin is indicated as a broad-spectrum anti-parasitic for the treatment of intestinal strongyloidiasis caused by _Strongyloides stercoralis_ and onchocerciasis caused by _Onchocerca volvulus_. Systemic ivermectin therapy is used internationally for the treatment of various tropical diseases, including filariasis, cutaneous larva migrans, and _Loa loa_ infection, amongst others. FDA Label Treatment of rosacea Mechanism of Action Ivermectin binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of the microfilaria. This binding causes an increase in the permeability of the cell membrane to chloride ions and results in hyperpolarization of the cell, leading to paralysis and death of the parasite. Ivermectin also is believed to act as an agonist of the neurotransmitter gamma-aminobutyric acid (GABA), thereby disrupting GABA-mediated central nervous system (CNS) neurosynaptic transmission. Ivermectin may also impair normal intrauterine development of _O. volvulus_ microfilariae and may inhibit their release from the uteri of gravid female worms. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 100~250 mg/mL ( 114.27~285.68 mM ) Ethanol : ~100 mg/mL H2O : < 0.1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.86 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 25.0 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (2.38 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.86 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1427 mL | 5.7136 mL | 11.4273 mL | |
| 5 mM | 0.2285 mL | 1.1427 mL | 2.2855 mL | |
| 10 mM | 0.1143 mL | 0.5714 mL | 1.1427 mL |