AGE AND GENDER INFLUENCE THE STEREOSELECTIVE PHARMACOKINETICS OF PROPRANOLOL

The eff ect of age and gender on the stereoselective pharmacokinetics of propranolol was studied in 12 young (25 to 33 years old) and 12 elderly (62 to 79 years old) healthy nonsmoking volunteers, half of whom were female. Racemic propranolol was administered (80 mg p.oz.) each 8 hr for seven doses. Serum was obtained just before (0 time) and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after the final dose and analyzed for propranolol enantiomers. The serum concentration of alpha-1 acid glycoprotein was determined before propranolol administration. The binding of each enantiomer to serum proteins was determined in samples obtained before propranolol administration and two hr after the final dose of propranolol. We found that the intrinsic hepatic clearance of S-propranolol was about 30% smaller in the elderly than in the young, whether it was calculated for total or unbound drug. Additionally, the elimination half-lives of both enantiomers were 2- to 3-fold prolonged in the elderly compared with the young. In all subjects regardless of age or sex the intrinsic hepatic clearance of the total (bound plus free) S-isomer was smaller than that of the R-isomer. There was no age-related difference in alpha-1 acid glycoprotein concentration or protein binding of either enantiomer of propranolol. However, there was a gender-related difference with the females having significantly greater binding of the S-enantiomer than the males. Also only the females displayed a stereoselective difference in the intrinsic hepatic clearance of the unbound enantiomers with that for the S-enantiomer being about 40% greater than that for the R-enantiomer. These data emphasize that stereoselective pharmacokinetic and binding studies are required before any age-and gender-related differences in propranolol sensitivity are attributed to pharmacodynamic rather than pharmacokinetic causes.