Haloperidol Disposition Is Dependent on Debrisoquine Hydroxylation Phenotype

Abstract

To investigate the importance of genetic factors for the regulation of haloperidol metabolism, we studied the disposition of a single oral dose of this drug in a panel of six extensive (EM) and six poor (PM) metabolizers of de-brisoquine. PM eliminated haloperidol significantly slower than EM, the plasma half-life being longer (mean 29.4 ± S.D. 4.2 and 16.3 ± 6.4 h; p < 0.01) and the clearance lower (1.16 ± 0.36 and 2.49 ± 1.31 L/h/kg; p < 0.05). A 4-mg dose of haloperidol was given to the first three PM, but all three developed side effects, and a 2-mg dose had to be given to the next three PM subjects. All EM received 4 mg haloperidol. The disposition of haloperidol is thus associated with the genetically determined capacity to hydroxylate debrisoquine. PM of debrisoquine (7% of Caucasian populations) might, therefore, on common doses of haloperidol, achieve high plasma concentrations and thereby have an increased risk of side effects. At the other extreme, very rapid metabolizers may need increased doses of haloperidol.