By what organ is ivermectin primarily filtered?

Ivermectin Renal Filtration and Excretion

Ivermectin is primarily excreted in the feces, with less than 1% of the administered dose excreted in the urine. 1

Pharmacokinetics of Ivermectin

Absorption and Distribution

• After oral administration, ivermectin plasma concentrations are approximately proportional to the dose 1
• Following a standard high-fat meal, ivermectin bioavailability increases approximately 2.5-fold compared to administration in the fasted state 1
• After single 12-mg doses in fasting healthy volunteers, peak plasma concentrations occur at approximately 4 hours after dosing 1

Metabolism

• Ivermectin is extensively metabolized in the liver 1, 2
• The primary enzyme responsible for ivermectin metabolism is cytochrome P450 3A4 (CYP3A4) 1, 2, 3
• CYP3A5 also contributes to ivermectin metabolism but to a significantly lesser extent 2, 3
• Thirteen different metabolites (M1-M13) have been identified, with three major metabolites (M1, M3, and M6) found in microsomes, hepatocytes, and blood after oral administration 2
• The main human metabolites are:
  • M1 (3″-O-demethyl ivermectin) - produced primarily by CYP3A4 2
  • M3 (4-hydroxymethyl ivermectin) - produced primarily by CYP3A4 2
  • M6 (3″-O-demethyl, 4-hydroxymethyl ivermectin) - produced primarily by CYP3A4 2

Elimination

• Ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days 1
• Less than 1% of the administered dose is excreted in the urine 1
• The plasma half-life of ivermectin in humans is approximately 18 hours following oral administration 1
• Some metabolites have longer half-lives than the parent compound, with M1 (54.2 ± 4.7 h) and M4 (57.5 ± 13.2 h) having considerably longer half-lives than ivermectin (38.9 ± 20.8 h) 4

Special Considerations in Specific Populations

Renal Impairment

• Since ivermectin is primarily eliminated through fecal excretion and minimally through renal excretion, dosage adjustments are not required in patients with renal impairment 5
• Ivermectin has limited ovicidal activity, and a second dose is often recommended 14 days after the first dose to ensure complete eradication of parasites 5

Hepatic Impairment

• Patients with severe liver disease may be at higher risk for toxicity as the safety of ivermectin in this population is not well established 6
• The safety and pharmacokinetics of ivermectin among persons with liver disease have been evaluated only after single-dose administration 5
• For persons with severe liver dysfunction, caution should be exercised as metabolism may be impaired 6

Mechanism of Action

• Ivermectin is a member of the avermectin class of broad-spectrum antiparasitic agents 1
• It binds selectively to glutamate-gated chloride ion channels in invertebrate nerve and muscle cells 1, 7
• This binding increases the permeability of the cell membrane to chloride ions, causing hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite 1
• Ivermectin may also interact with other ligand-gated chloride channels, such as those gated by gamma-aminobutyric acid (GABA) 1, 7
• The selective activity of ivermectin is attributable to the fact that some mammals do not have glutamate-gated chloride channels and that ivermectin has a low affinity for mammalian ligand-gated chloride channels 1
• Additionally, ivermectin does not readily cross the blood-brain barrier in humans 1, 7

Clinical Implications

• Ivermectin should be taken with food to increase bioavailability 5
• Adjustments to ivermectin dosing are not required in patients with renal impairment 5
• The safety of multiple doses in patients with severe liver disease is not known 5
• Ivermectin should not be used in children who weigh less than 15 kg due to potential neurotoxicity 5
• There is no role for ivermectin in the treatment of CNS infections as it does not reach sufficient concentrations in cerebrospinal fluid 5

In conclusion, ivermectin undergoes extensive hepatic metabolism via CYP3A4 and is primarily eliminated through fecal excretion, with minimal renal excretion.