2019A14 Describe the metabolism and excretion of tramadol, including the
implications for clinical practice.

· Metabolism

· Excretion

· Polymorphism

Rate	· Clearance 3.7mL/kg/min · t_1/2_β 6 hours for tramadol, 7 hours for M1
Phase 1	· CYP2D6: -> O-desmethyltramadol (M1, 4x analgesic efficacy) · CYP3A4: -> N-desmethyltramadol (M2)
Phase 2	· Glucuronidation of tramadol, M1, M2
Active metabolite	· +M1: 4 x more active at μ opioid receptor, no serotonergic activity o i.e. tramadol is a pro-drug · -M1: noradrenaline reuptake inhibitor

Route

· Into urine 90%

o As parent – 30%

o As metabolite – 60%

· Into bile 10%

Rate

· ∝ GFR

Significance

· Renal failure -> accumulation of tramadol and M1 (and inactive metabolites)

Intermediate and poor metaboliser

· One or two defective alleles respectively

· Common in Hong Kong Chinese (~30%)

· ↓Analgesia

· ↑5-HT effects: nausea/vomiting, risk serotonin syndrome

Ultra-rapid metaboliser

· More than two effective alleles

· Common in North Africans and Arabs (~30%)

· ↑Analgesia, ↑toxicity e.g. respiratory depression, sedation