Ivermectin Metabolism
Ivermectin is metabolized primarily in the liver by the cytochrome P450 3A4 enzyme (CYP3A4), with minor contributions from CYP3A5 and CYP2D6, and the drug and its metabolites are excreted almost exclusively in the feces (>99%), with less than 1% excreted in urine. 1
Primary Metabolic Pathway
The hepatic metabolism of ivermectin occurs through two main reactions:
- O-demethylation - producing M1 (3″-O-demethyl ivermectin)
- C-hydroxylation - producing M3 (4-hydroxymethyl ivermectin)
CYP3A4 is responsible for generating both major metabolites, with CYP3A5 contributing to a lesser extent in M1 formation 2, 3. Studies using human liver microsomes and recombinant CYP450 enzymes confirmed that CYP3A4 is the predominant isoform, with approximately 90% inhibition of metabolism when anti-CYP3A4 antibodies were used 3.
Metabolite Profile
At least 10-13 different metabolites have been identified in human studies 2, 3. The three major metabolites found in human liver microsomes, primary hepatocytes, and whole blood after oral administration are:
- M1 (3″-O-demethyl ivermectin) - demethylated product
- M3 (4-hydroxymethyl ivermectin) - hydroxylated product
- M6 (3″-O-demethyl, 4-hydroxymethyl ivermectin) - combined demethylation and hydroxylation
These structures were confirmed using LC-MS/MS and nuclear magnetic resonance spectroscopy 2.
Excretion and Elimination
Ivermectin and its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in urine 1. The plasma half-life is approximately 18 hours following oral administration 1.
Clinical Implications for Drug Interactions
CYP3A4 Inhibitors
Drugs that inhibit CYP3A4 can significantly increase ivermectin concentrations. Azithromycin can significantly increase serum ivermectin concentration 4. Ketoconazole, a specific CYP3A4 inhibitor, improved ivermectin efficacy in experimental models by reducing metabolism 5.
CYP3A4 Inducers
Metabolism is induced by anticonvulsants and steroids 4, which can reduce ivermectin plasma levels and potentially decrease efficacy.
Hepatic Impairment
Caution is warranted in reduced hepatic function 4, as the liver is the primary site of metabolism. The safety of multiple doses in patients with severe liver disease is not well established 6.
Important Pharmacokinetic Considerations
Food significantly affects absorption: Administration with a high-fat meal results in an approximate 2.5-fold increase in bioavailability compared to fasted state 1. The 2015 CDC guidelines note that ivermectin should be taken with food because bioavailability is increased, thereby increasing penetration of the drug into the epidermis 6.
Renal impairment: Adjustments to ivermectin dosing are not required in patients with renal impairment 6, given the minimal urinary excretion.
CNS penetration: Ivermectin does not readily cross the blood-brain barrier in humans under normal circumstances 1. This is clinically relevant as there is no role for ivermectin in the treatment of CNS infections as it does not reach sufficient concentrations in CSF 4.