Km. Sowinski et Bs. Burlew, IMPACT OF CYP2D6 POOR METABOLIZER PHENOTYPE ON PROPRANOLOL PHARMACOKINETICS AND RESPONSE, Pharmacotherapy, 17(6), 1997, pp. 1305-1310
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 hea
lthy men with CYP2D6 poor metabolizer (PM) phenotype. Subjects receive
d R,S-propranolol hydrochloride 80 mg every 8 hours for 16 doses. Afte
r the sixteenth dose, blood and urine samples were collected for 24 ho
urs, and serum propranolol and urine metabolite concentrations were de
termined by chiral high-performance liquid chromatography. Heart rate
response to treadmill exercise was measured serially over 24 hours. Ap
parent oral clearance of propranolol and partial metabolic clearance v
alues of propranolol to 4-hydroxypropranolol (HOP), propranolol glucur
onide, and naphloxylactic acid (NLA) were estimated. Apparent oral cle
arance and elimination half-life of propranolol were not different bet
ween EMs and PMs. Partial metabolic clearance of propranolol to HOP wa
s 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 eff
ect 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.