Racial differences in propranolol enantiomer kinetics following simultaneous i.v. and oral administration.
1. Racial differences in propranolol enantiomer kinetics following oral dosing were previously documented in our laboratory. The purpose of this study was to more completely describe propranolol kinetics in black and white subjects with the goal of gaining a better understanding of the mechanism(s) responsible for racial differences in oral propranolol kinetics. 2. Twelve white and 13 black healthy males were included in the study. Poor metabolizers of dextromethorphan and mephenytoin were excluded. Subjects took oral propranolol 80 mg every 8 h for 16 doses and received an intravenous dose of radiolabelled propranolol with the 16th dose. Serum and urine samples were collected for 24 h after the 16th dose. Serum concentrations of R- and S-propranolol and urine concentrations of its three primary metabolites were determined by h.p.l.c. 3. Apparent oral clearances of R- and S-propranolol were higher (P < 0.05) in blacks than whites (R-propranolol: 5036 +/- 4175 ml min-1 vs 2854 +/- 879 ml min-1; S-propranolol 3255 +/- 1723 ml min-1 vs 2125 +/- 510 ml min-1; blacks vs whites). 4. R- and S-propranolol clearances were higher in blacks than whites (R-propranolol 1069 +/- 316 ml min-1 vs 841 +/- 161 ml min-1; S-propranolol 947 +/- 271 ml min-1 vs 771 +/- 142 ml min-1; blacks vs whites, P < 0.05). 5. There were trends (P > 0.05 < 0.10) toward higher side chain oxidation, 4-hydroxylation and R-propranolol glucuronidation in blacks compared with whites. Ethnic differences in the enantiomeric ratios of partial metabolic clearance values were not observed. 6. We conclude the higher propranolol oral clearances in black subjects are explained by blacks having slightly higher hepatic metabolism via all three of its major metabolic pathways. Higher propranolol clearances among black subjects were also observed and we conclude this finding is explained largely by the higher hepatic metabolism, but also by slightly higher liver blood flow among black subjects.
Sowinski
K M
KM
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis, USA.
Lima
J J
JJ
Burlew
B S
BS
Massie
J D
JD
Johnson
J A
JA
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D044383:Black People; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D011433:Propranolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D044465:White People
D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D019389:Cytochrome P-450 CYP2D6