STEREOSELECTIVE INCREASE OF PLASMA-CONCENTRATIONS OF THE ENANTIOMERS OF PROPRANOLOL AND ATENOLOL DURING EXERCISE

Objective: In vitro studies have shown that, like catecholamines, both propranolol and atenolol are taken up by and released from adrenergic cells. We performed this study to investigate whether this may also p lay a role in humans and whether stereoselective aspects are important . Methods: This was a randomized, double-blind, placebo-controlled, cr ossover study of two groups of 12 healthy volunteers. Subjects receive d single oral doses of 80 mg (R,S)-, 40 mg (R)-, and 40 mg (S)-propran olol; 100 mg (R,S)-, 50 mg (R)-, and 50 mg (S)-atenolol; and placebo a t intervals of 1 week. Exercise was performed at 4 and 9 hours after d rug intake, and blood samples were taken before and at the end of each exercise period. The plasma concentrations of the (R)- and (S)-enanti omers of propranolol and atenolol, as well as those of epinephrine and norepinephrine, were determined by HPLC. Results: Effects of exercise on the plasma levels of the enantiomers of propranolol and atenolol w ere similar. When the optically pure enantiomers were administered, ex ercise caused a marked and significant increase of the plasma concentr ations of the (S)- but not of the (R)-enantiomers. When the drugs were administered in the racemic form, the plasma levels of both the (R)- and (S)-enantiomers were elevated to the same extent. The increase of norepinephrine levels during exercise was more pronounced than that of epinephrine and paralleled that of the (S)-enantiomers of the beta-bl ockers. Conclusion: Bearing the in vitro data in mind, we conclude tha t (S)-propranolol and (S)-atenolol are taken up into and released from adrenergic cells together with norepinephrine during exercise. The re ason why the plasma concentrations of (R)-propranolol and (R)-atenolol are increased only during exercise in the presence of the correspondi ng (S)-enantiomers remains to be determined.