Carvedilol is a mixed alpha- and beta-adrenergic receptor antagonist that is administered as a racemic mixture. Although the two isomers are equally potent as alpha 1-blockers the S(-)-isomer is principally responsible for the beta blockade of carvedilol. To determine the role of pharmacogenetics in the metabolism of carvedilol we studied nine extensive metabolizers of both debrisoquin and mephenytoin, seven poor metabolizers of debrisoquin but extensive metabolizers of mephenytoin, and three poor metabolizers of mephenytoin but extensive metabolizers of debrisoquin. The clearance of R-carvedilol was significantly lower than S-carvedilol in both debrisoquin phenotypes. Poor metabolizers of debrisoquin had a significantly lower clearance of R-carvedilol than extensive metabolizers of debrisoquin. The partial metabolic clearance of carvedilol to the two ring-hydroxylated metabolites 4- and 5-hydroxyphenyl carvedilol were significantly reduced in poor metabolizers of debrisoquin. No effect of mephenytoin phenotype on carvedilol kinetics was observed. Thus carvedilol is stereoselectively metabolized in humans, and the clearance of S-carvedilol is higher than that of R-carvedilol. In poor metabolizers of debrisoquin the clearance of R-carvedilol is further reduced, resulting in higher plasma concentrations and perhaps greater alpha-blockade.