Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects

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Abstract
This study determined the total clearance of propranolol and the partial clearances through each of its three primary metabolic pathways after administration of an 80 mg single oral dose in 28 young, white subjects (13 women; 15 men). The oral clearance of propranolol was significantly higher 63%, p < 0.02) in the men (65.7 .+-. 7.7 ml/min/kg; mean .+-. SE) than in the women (40.2 .+-. 6.2 ml/min/kg). This sex difference was mainly attributable to a 137% higher clearance through the P-450-medicated side-chain oxidation in the men (p < 0.001). There was also a 52% higher clearance through glucuronidation in the men (p < 0.02). In contrast, the clearance through the P-450-mediated ring oxidation was not different between men and women. After administration of simultaneous intravenous doses of hexadeuterium-labeled drug (0.1 mg/kg) to 11 of the subjects, there were no differences between men and women in volume of distribution or half-life. Moreover, there were no sex differences in plasma and blood binding of propranolol. This study was thus demonstrates that higher plasma levels of propranolol occur in women than in men after oral doses and suggests that some drug metabolizing enzymes, but not others, are regulated by sex hormones in human beings.