Half-Life of Loperamide (Immodium)
The elimination half-life of loperamide is approximately 10.8 hours, with a range of 9.1 to 14.4 hours. 1
Pharmacokinetic Properties of Loperamide
Absorption and Distribution
- Loperamide has low oral absorption, with plasma concentrations of unchanged drug remaining below 2 ng/mL after intake of a 2 mg capsule 1
- Peak plasma concentrations occur approximately 5 hours after administration of the capsule and 2.5 hours after liquid formulation 1
- Loperamide is highly protein-bound, with approximately 95% binding to plasma proteins 1
- It is a substrate for P-glycoprotein, which affects its distribution 1
Metabolism
- Loperamide is primarily metabolized through oxidative N-demethylation 1
- The metabolism occurs mainly via cytochrome P450 isozymes CYP2C8 and CYP3A4, with CYP2B6 and CYP2D6 playing minor roles 1
- In vitro studies have shown that CYP3A4 inhibitors (like ketoconazole) can inhibit the N-demethylation process by up to 90%, potentially increasing loperamide exposure 1
Elimination
- Excretion of unchanged loperamide and its metabolites occurs primarily through the feces 1
- The drug has minimal central nervous system effects due to its low oral absorption and inability to cross the blood-brain barrier 2
Clinical Implications of Loperamide's Half-Life
Dosing Considerations
- Loperamide's relatively long half-life allows for effective symptom control with intermittent dosing 3
- For acute diarrhea, the recommended initial dose is 4 mg followed by 2 mg after each unformed stool, not exceeding 16 mg per day 3
- The drug takes 1-2 hours to reach its therapeutic effect, so additional dosing should be spaced accordingly to avoid rebound constipation 3
Special Populations
- In patients with hepatic dysfunction, loperamide clearance may be impaired, potentially leading to higher plasma concentrations 1
- No specific dosage adjustments are mentioned for renal impairment, as the drug is primarily eliminated through hepatic metabolism and fecal excretion 1
Safety Considerations
- Due to its long half-life, accumulation can occur with repeated dosing, particularly in patients with hepatic impairment 1
- Concomitant use with CYP3A4 or CYP2C8 inhibitors can increase loperamide exposure and potentially lead to adverse effects 1
- At therapeutic doses, loperamide has minimal central nervous system effects due to its limited ability to cross the blood-brain barrier 2
- However, at very high doses (exceeding recommended amounts), loperamide can cause opioid-like effects and potentially serious cardiac complications 4
The pharmacokinetic profile of loperamide, particularly its half-life of approximately 11 hours, contributes to its efficacy as an antidiarrheal agent while allowing for convenient dosing schedules in the management of acute and chronic diarrhea.