Fentanyl is primarily metabolized in which organ by which enzyme?

• A. In the liver by CYP3A4
• B. In the kidney by CYP2D6
• C. In the lungs by CYP1A2
• D. In the spleen by glucuronidation

Answer: (A)

Fentanyl is cleared mainly by the liver through metabolism by the cytochrome P450 system, with CYP3A4 being the primary enzyme responsible. Its major metabolic step is N-dealkylation to norfentanyl, a process that occurs predominantly in hepatocytes. Because of this hepatic pathway, kidney excretion of unchanged drug is minimal and CYP2D6 or CYP1A2 do not play the central roles in its metabolism. Glucuronidation can occur on metabolites later, but it isn’t the main route of clearance. Clinically, that means drugs that inhibit CYP3A4 can raise fentanyl levels and intensify or prolong effects, while inducers can lower exposure.