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1 The objective of this study was to elucidate stereoselective mechanisms of propranolol metabolism in man. Five normal subjects were given single 80 mg oral doses of deuterium-labeled pseudoracemates of propranolol, and the stereochemical composition of propranolol and its major metabolites in urine was determined by GC/MS. 2 The (-)/(+)-enantiomer ratios for unchanged propranolol, 1.50 + 0.10 (mean ± s.e. mean), and propranolol glucuronide, 1.76 + 0.10, were similar to previous findings in plasma. 3 All products of side-chain oxidation also consisted mainly of the (-)-enantiomer, with an overall (-)/(+) ratio of 1.61 + 0.11. 4 A (-)/(+) ratio of 1.04 + 0.17 for 4-hydroxypropranolol did not indicate stereoselectivity in ring oxidation. However, the ratio for its glucuronic acid conjugate of 1.78 ± 0.19 and for its sulphate conjugate of 0.27 ± 0.03 suggested stereoselectivity in either the glucuronidation or sulphation of 4-hydroxypropranolol, or both. 5 When the stereoselectivity in these secondary pathways was taken into consideration, the overall ring oxidation strongly favoured (+)-propranolol with a (-)/(+)-enantiomer ratio of 0.59 ± 0.09.6 The composite observations of the stereochemistry of propranolol metabolism in man are consistent with stereoselective ring oxidation of (+)-propranolol, leading to a greater bioavailability of the pharmacologically more active (-)-propranolol and subsequent preferential side-chain oxidation and glucuronidation of this enantiomer.

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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 ,ug day-') 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 ao-acid glycoprotein from 0.54 ± 0.11 mg ml-' in control to 0.37 ± 0.08 mg ml-' (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).

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