The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers

1. Plasma binding of tritium‐labelled racemic propranolol (P) was measured by equilibrium dialysis. The unbound enantiomers were separated by h.p.l.c. after chiral derivatization. The binding of (‐)‐P was higher than that of (+)‐P. 2. Contrary to previous suggestions, a sex difference in the plasma binding of the P enantiomers (9 young women, 12 young men) was not observed. The unbound percentage of (‐)‐P was 9.2 +/‐ 1.8 (mean +/‐ s.d.) in women vs 9.1 +/‐ 1.7 in men; for (+)‐ P it was 10.8 +/‐ 1.8 vs 10.8 +/‐ 2.1. 3. In the nine women, the binding did not change with fluctuating plasma oestradiol concentrations during the menstrual cycle. Testosterone cypionate doubled the circulating concentrations of testosterone in eight men but had no effect on P binding. 4. Ethinyl oestradiol (50 micrograms day‐1) alone or together with norethindrone (OCD) in eight of the women produced an increase in the unbound percentage of both (‐)‐P (11.4 +/‐ 2.6 vs 9.5 +/‐ 1.6 for control; P < 0.001) and (+)‐P (13.2 +/‐ 2.5 vs 11.2 +/‐ 1.5 for control; P < 0.001). This was due to a decrease in the plasma concentrations of alpha 1‐acid glycoprotein from 0.54 +/‐ 0.11 mg ml‐1 in control to 0.37 +/‐ 0.08 mg ml‐1 (P < 0.001) during ethinyl oestradiol treatment. 5. Enantioselectivity in the unbound fraction of P increased with increasing total binding from a (‐)/(+)‐ratio of 0.93 at 84% binding to a (‐)/(+)‐ratio of 0.78 at 94% binding (P < 0.001).