Racial differences in propranolol enantiomer kinetics following simultaneous i.v. and oral administration

Abstract

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.

Measurement of Binding of Basic Drugs to Acidic Phospholipids Using Surface Plasmon Resonance and Incorporation of the Data into Mechanistic Tissue Composition Equations to Predict Steady-State Volume of Distribution

“…The binding of the two enantiomers to phosphatidylserine was similar (K D 117 Ϯ 10 and 122 Ϯ 12 M for the R-and S-enantiomer, respectively). This result is in line with literature data showing only small differences in the blood/serum concentration ratio, unbound volume of distribution at steady state (V ss u ) (V ss / fraction unbound in plasma), and calculated acidic phospholipid binding for the two enantiomers in white and African-American subjects (Sowinski et al, 1996). The blood/serum concentration ratio was 0.87 and 0.86 for R-and S-propranolol, respectively, in African-American subjects and 0.89 and 0.86, respectively, in white subjects.…”

Why do hypertensive patients of African ancestry respond better to calciumblockers and diuretics than to ACE inhibitors and β-adrenergic blockers? Asystematic review

“…Oral clearance of L-propranolol was reported to be similar [56], or higher in persons of African, than in persons of European, ancestry (respectively 28 ml/min/kg, SD 8; vs 21, SD 7; P <0.05) [52], with similar, or up to 25% lower peak plasma concentrations [52,56]. In line with this, hepatic metabolism of propranolol via side chain oxidation, 4-hydroxylation or R-propranolol glucuronidation was observed to be higher in persons of African than in those of European ancestry [44]. However, propranolol clearance after intravenous infusion (0.1 mg/kg), was similar in one study [61].…”

Characterization of Cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 Activities toward Model CYP2D6 Substrates Dextromethorphan, Bufuralol, and Debrisoquine

“…Population phenotyping studies imply that metabolism and thus clearance of CYP2D6 substrates may be reduced in African Americans relative to Caucasians, and this appears to be the case for nortriptyline. However, clearance of metoprolol appears to be similar and the clearance of propranolol (Sowinski et al, 1996), by both CYP1A2 and CYP2D6 (Johnson et al, 2000), is increased in African Americans compared with Caucasians. Thus, clearer insights into the consequences of existing and yet undiscovered population-specific alleles on a broad range of individual substrates are necessary to optimize pharmacotherapy of CYP2D6 substrates in individuals of black African origin.…”