1. Blood plasma and urine excretion pharmacokinetics of the (+) and (-) enantiomers of perhexiline have been determined in oral single-dose studies in eight human volunteers, and compared with the pharmacokinetics of the racemate drug in the same subjects. The (-) enantiomer is more rapidly metabolized and eliminated, and is stereoselectively hydroxylated to thecis-monohydroxy-perhexiline.2. The peak plasma concn of unchanged perhexiline is greater, while that of thecis-monohydroxy-perhexiline metabolite is lower, after administration of the (+) enantiomer than after the (-) enantiomer or the racemate. Similarly, theAUCvalues for unchanged perhexiline and for thetrans-monohydroxy-perhexiline metabolite are greatest and theAUCvalue for thecis-monohydroxy-perhexiline metabolite is lowest for the (+) enantiomer. The three stereoisomeric forms of perhexiline all had the same times to peak plasma concn of the unchanged drug or of thecis-metabolite, and all three forms had a similar plasma elimination half-life for unchanged perhexiline.3. Metabolism of racemic perhexiline to thecis-monohydroxy metabolite is the major mechanism of elimination of the drug in man and has been shown to be polymorphic in human populations. The (−) enantiomer which shows stereoselective metabolism to thecismetabolite might therefore show a greater polymorphic effect.4. Studies with rat-liver microsomal preparationsin vitroshowed that, in contrast to the human studiesin vivo, hydroxylation of perhexiline yields mostly thetrans-monohydroxy metabolite. The DA strain of rats exhibited slower rates of hydroxylationin vitrothan Wistar or Lewis strains of rats.