Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers.
We have previously shown that the disposition of haloperidol is decreased in poor (PM) compared to extensive (EM) metabolizers of debrisoquine. We now report that the plasma levels of the reduced metabolite of haloperidol, after a single 2- or 4-mg oral dose of the parent drug, are significantly higher in PM than in EM of debrisoquine. As PM have higher concentrations of haloperidol than EM, more of the reduced metabolite should be formed, since the formation of reduced haloperidol from haloperidol seems to be independent of the debrisoquine hydroxylase (cytochrome P4502D6) activity. Another reason to explain the increased metabolite levels in PM may be a decreased reoxidation of the reduced metabolite to haloperidol, as this reaction is catalyzed by cytochrome P4502D6. A third reason might be that reduced haloperidol is transformed to other metabolites by this enzyme.
Llerena
A
A
Department of Pharmacology and Psychiatry, University of Extremadura, Badajoz, Spain.
Dahl
M L
ML
Ekqvist
B
B
Bertilsson
L
L
D002851:Chromatography, High Pressure Liquid; D003647:Debrisoquin / Q000493:pharmacokinetics*; D006220:Haloperidol / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006900:Hydroxylation; D010084:Oxidation-Reduction; D010641:Phenotype
C040692:4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol; D006220:Haloperidol; D003647:Debrisoquin