Stereoselective pharmacokinetics of perhexiline.
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 the cis-monohydroxy-perhexiline. The peak plasma concn of unchanged perhexiline is greater, while that of the cis-monohydroxy-perhexiline metabolite is lower, after administration of the (+) enantiomer than after the (-) enantiomer or the racemate. Similarly, the AUC values for unchanged perhexiline and for the trans-monohydroxy-perhexiline metabolite are greatest and the AUC value for the cis-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 the cis-metabolite, and all three forms had a similar plasma elimination half-life for unchanged perhexiline. Metabolism of racemic perhexiline to the cis-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 the cis metabolite might therefore show a greater polymorphic effect. Studies with rat-liver microsomal preparations in vitro showed that, in contrast to the human studies in vivo, hydroxylation of perhexiline yields mostly the trans-monohydroxy metabolite. The DA strain of rats exhibited slower rates of hydroxylation in vitro than Wistar or Lewis strains of rats.
D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D010480:Perhexiline / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010480:Perhexiline