Tramadol is a substrate for which cytochrome P450 enzymes?

• A. CYP3A4 and CYP2C9
• B. CYP1A2 and CYP2D6
• C. CYP2E1 and CYP3A5
• D. CYP2C19 and CYP4A11

Answer: (A)

Tramadol’s metabolism hinges on two cytochrome P450 enzymes. The important one is CYP2D6, which converts tramadol into O-desmethyltramadol, a metabolite with strong analgesic activity. The other is CYP3A4, which forms N-desmethyltramadol, a less potent metabolite. Because of this, a person’s CYP2D6 activity and any drugs that inhibit or induce CYP2D6 or CYP3A4 can significantly alter tramadol’s effectiveness and risk of side effects. For example, poor CYP2D6 metabolizers may get less pain relief, while inhibitors or inducers of these enzymes can change both the level of tramadol and its active metabolites. Other enzymes listed are not the primary pathways for tramadol metabolism.