The Natural Precursor: Avermectins
Ivermectin's origin is tied to the natural world, beginning with a soil bacterium found in Japan in the 1970s by microbiologist Satoshi Ōmura. This bacterium, named Streptomyces avermitilis, was discovered to produce a class of compounds called avermectins through fermentation.
During this time, Ōmura collaborated with parasitologist William Campbell at the pharmaceutical company Merck & Co., Inc.. Campbell and his team screened the compounds from Ōmura's soil samples and identified the potent antiparasitic properties of avermectins. For their foundational work, the two scientists were jointly awarded the Nobel Prize in Physiology or Medicine in 2015.
From Avermectin to Ivermectin: The Semisynthetic Process
To create a more effective and safer drug for treating parasites in animals and, later, humans, scientists chemically modified the natural avermectin compounds. The key step is a targeted hydrogenation process that converts avermectin B1 into its dihydro derivative, which is ivermectin. This process modifies a specific double bond in the molecule, resulting in a product with improved pharmacological properties.
The Chemical Composition of Ivermectin
Ivermectin itself is not a single molecule but a mixture of two closely related homologous compounds, which are often produced in a consistent ratio during the manufacturing process.
- 22,23-dihydroavermectin B1a: This is the major component of the mixture, typically making up at least 80% of the final product.
- 22,23-dihydroavermectin B1b: This is the minor component, comprising less than 20% of the mixture.
Both homologs have very similar antiparasitic activity. The overall chemical structure of ivermectin is a sixteen-membered macrocyclic lactone disaccharide, meaning it is a large molecule with a large lactone ring structure and two attached sugar molecules. The final product is a white or yellowish-white crystalline powder.
Chemical Properties and Formulations
Ivermectin's chemical properties influence how it is formulated and administered. Its highly lipophilic nature means it is poorly soluble in water. This is why it is formulated with other agents and is much more soluble in organic solvents like methanol and ethanol. This insolubility in water is also relevant to its mechanism of action, helping to explain why it does not easily cross the blood-brain barrier in most mammals, contributing to its safety profile.
For human use, ivermectin is formulated into oral tablets, while topical formulations like lotions and creams are used for certain skin conditions. Veterinary formulations are available in various forms, including oral drenches, pour-ons, and injections.
Ivermectin vs. Avermectin: Key Differences
To understand what ivermectin is made of, it is essential to distinguish it from its natural starting point, avermectin. The following table compares the two compounds:
| Feature | Avermectin | Ivermectin |
|---|---|---|
| Source | Natural fermentation product from the soil bacterium Streptomyces avermitilis | Semisynthetic, derived by chemically modifying avermectin B1 |
| Synthesis | Produced by bacteria | Created through a chemical hydrogenation process performed by a pharmaceutical company |
| Composition | An unsaturation at the C22–C23 position | Dihydro derivative, meaning the double bond at C22–C23 has been reduced |
| Activity | Potent antiparasitic activity | Enhanced efficacy and safety, with higher potency and wider margin of safety than its precursor |
| Classification | Macrocyclic lactone | Also a macrocyclic lactone, but with a slight structural modification |
Why is ivermectin not an antibiotic?
Despite being derived from a bacterium, ivermectin is an antiparasitic drug, not a traditional antibacterial antibiotic. This is because its mechanism of action is highly selective for invertebrates, not bacteria.
Ivermectin works by binding to and activating glutamate-gated chloride ion channels in the nerve and muscle cells of susceptible parasites. This action causes an influx of chloride ions, leading to hyperpolarization of the cell membrane, which results in paralysis and death of the parasite.
Mammals do not have these same glutamate-gated chloride channels. Furthermore, ivermectin does not easily cross the blood-brain barrier in most mammals, which is where gamma-aminobutyric acid (GABA)-gated chloride channels (which ivermectin also interacts with) are located. This selective targeting is why ivermectin is generally safe for mammals when used correctly, despite its derivation from a bacterial fermentation product.
Conclusion
In summary, ivermectin is a semisynthetic drug, meaning it is partially natural and partially man-made. It is fundamentally based on a natural compound, avermectin, which is a metabolite produced by the soil bacteria Streptomyces avermitilis. Through a chemical hydrogenation process, avermectin is modified to become ivermectin, a mixture primarily composed of two dihydroavermectin homologs. This targeted chemical synthesis enhances the drug's safety and efficacy, leading to its widespread use as a vital antiparasitic in both human and veterinary medicine. The story of its creation, from a humble soil microorganism to a "wonder drug," underscores the remarkable process of modern pharmacology. The authoritative drug information resource Drugs.com provides comprehensive details on its clinical use and properties.
