From the Guidelines
Modafinil is primarily metabolized by the liver through the cytochrome P450 3A4 (CYP3A4) enzyme, with minor contributions from CYP1A2, CYP2B6, and CYP2C19, as indicated by its classification as a CYP3A4 inducer 1.
Metabolism Pathways
The metabolism of modafinil involves hydrolysis, oxidation, and conjugation pathways, resulting in the formation of two major metabolites: modafinil acid and modafinil sulfone. These metabolites are pharmacologically inactive and are eventually eliminated from the body.
Elimination
Most of modafinil and its metabolites (around 80%) are excreted through urine, with a smaller portion eliminated via feces. The drug has a half-life of about 12-15 hours, meaning it takes this time for half of the drug to be cleared from the system.
Clinical Considerations
Because modafinil is metabolized by liver enzymes, patients with severe liver impairment may require dose adjustments due to potentially decreased clearance of the medication. Additionally, modafinil can interact with other medications that are substrates, inducers, or inhibitors of the CYP450 enzyme system, potentially affecting their metabolism and effectiveness, as seen with other drugs metabolized by CYP3A4, such as cyclosporin A 1.
Key Points
- Modafinil is metabolized primarily by CYP3A4.
- It has a half-life of 12-15 hours.
- Approximately 90% of modafinil is converted to inactive metabolites.
- Modafinil and its metabolites are mainly excreted through urine.
- Liver impairment may require dose adjustments.
- Modafinil can interact with other CYP450 substrates, inducers, or inhibitors.
From the FDA Drug Label
The existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of modafinil tablets due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of modafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of modafinil. In vitro data demonstrated that modafinil weakly induces CYP1A2, CYP2B6, and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by modafinil.
Modafinil is metabolized through multiple pathways, including CYP3A enzymes and a non-CYP-related pathway. The main enzymes involved in modafinil metabolism are:
- CYP3A4: partially involved in the metabolic elimination of modafinil
- CYP1A2: weakly induced by modafinil
- CYP2B6: weakly induced by modafinil
- CYP2C19: reversibly inhibited by modafinil The non-CYP-related pathway is the most rapid in metabolizing modafinil 2.
From the Research
Metabolism of Modafinil
- Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine 3
- Less than 10% of the dose is excreted as unchanged drug 3
- Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways 3
Role of Cytochrome P450 Enzymes
- Modafinil can inhibit CYP2C19 activity, with a K(i) value of 39 microM 4
- Modafinil can also induce CYP1A2, CYP2B6, and CYP3A4 activities, although to a lesser extent 4
- Armodafinil, the pure R-enantiomer of racemic modafinil, is a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 5
Drug-Drug Interactions
- Modafinil can affect the pharmacokinetics of drugs that are metabolized by certain CYP enzymes, such as CYP2C19 and CYP3A4 3, 6
- Co-administration of modafinil with drugs that are substrates of CYP3A4 (e.g. ciclosporin, triazolam) and CYP2C19 enzymes (e.g. diazepam, phenytoin) may require dosage adjustments 5, 6