Impact of CYP2D6 Poor Metabolizer Phenotype on Propranolol Pharmacokinetics and Response

We conducted an open‐label study to determine the impact of cytochrome P‐4502D6 (CYP2D6) on propranolol pharmacokinetics and response in 12 healthy men with CYP2D6 extensive metabolizer (EM) phenotype and 3 healthy men with CYP2D6 poor metabolizer (PM) phenotype. Subjects received R,S‐propranolol hydrochloride 80 mg every 8 hours for 16 doses. After the sixteenth dose, blood and urine samples were collected for 24 hours, and serum propranolol and urine metabolite concentrations were determined by chiral high‐performance liquid chromatography. Heart rate response to treadmill exercise was measured serially over 24 hours. Apparent oral clearance of propranolol and partial metabolic clearance values of propranolol to 4‐hydroxypropranolol (HOP), propranolol glucuronide, and naphloxylactic acid (NLA) were estimated. Apparent oral clearance and elimination half‐life of propranolol were not different between EMs and PMs. Partial metabolic clearance of propranolol to HOP was significantly higher and to NLA was significantly lower in EMs than in PMs. No differences in percentage reductions in exercise heart rate were observed between EMs and PMs. The CYP2D6 PM phenotype has no effect on propranolol blood concentrations and does not alter response to propranolol. Our data also suggest that CYP2D6 mediates approximately 65% and 70% of S‐ and R‐propranolol's 4‐hydroxylation, respectively.