How is Duloxetine (Cymbalta) metabolized?

From the Guidelines

Duloxetine is primarily metabolized in the liver through the cytochrome P450 enzymes, particularly CYP1A2 and CYP2D6, as indicated by its potential interactions with drugs metabolized by these enzymes 1. The metabolism of duloxetine involves two main pathways: oxidation and conjugation.

• The drug undergoes extensive hepatic metabolism by cytochrome P450 enzymes, particularly CYP1A2 and CYP2D6, which convert it into numerous metabolites.
• CYP1A2 is responsible for the majority of duloxetine's metabolism, while CYP2D6 plays a secondary role, as suggested by the potential for drug-drug interactions with inhibitors of these enzymes 1. After metabolism, these metabolites are mainly excreted in urine with a smaller amount eliminated in feces.
• The metabolites of duloxetine are pharmacologically inactive. This hepatic metabolism explains why duloxetine should be used with caution in patients with hepatic impairment, such as those who develop jaundice or other evidence of clinically significant liver dysfunction, in which case duloxetine should be discontinued and not restarted 1. The use of duloxetine requires careful consideration of its metabolism and potential drug interactions to minimize the risk of adverse effects, particularly in patients with hepatic impairment or those taking other medications that may interact with CYP1A2 or CYP2D6 enzymes 1.

From the FDA Drug Label

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6 Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate

Duloxetine is extensively metabolized in the liver by two main enzymes: CYP1A2 and CYP2D6. The major metabolic pathways involve oxidation of the naphthyl ring, followed by conjugation and further oxidation. The main metabolites found in plasma are 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Only a small amount (<1%) of unchanged duloxetine is excreted in the urine, while about 70% of the dose appears in the urine as metabolites of duloxetine, and about 20% is excreted in the feces 2.

From the Research

Metabolism of Duloxetine

• Duloxetine is metabolized in the liver by cytochrome P450 (CYP) 1A2 and 2D6 3, 4, 5, 6
• The metabolites of duloxetine are inactive and mainly excreted in the urine 3
• The mean elimination half-life of duloxetine is approximately 12 hours 3
• Duloxetine is highly protein bound and widely distributed throughout tissues 3

Factors Affecting Metabolism

• Patient demographic characteristics such as sex, smoking status, age, ethnicity, CYP2D6 genotype, hepatic function, and renal function can influence the pharmacokinetics of duloxetine 4
• Impaired hepatic function or severely impaired renal function can affect the metabolism of duloxetine 4
• CYP1A2 inhibition can increase duloxetine exposure to a clinically significant degree 4, 5
• CYP2D6 inhibitors or poor metabolizers can increase the exposure of duloxetine, but to a lesser extent than CYP1A2 inhibition 4, 6

Drug Interactions

• Concomitant use of duloxetine and potent CYP1A2 inhibitors should be avoided 3, 5
• Duloxetine should be used with caution in patients receiving drugs that are extensively metabolized by CYP2D6, particularly those with a narrow therapeutic index 3
• Duloxetine can increase the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2 4