NONLINEAR RELATIONSHIP BETWEEN CIRCULATING CONCENTRATIONS OF REDUCED HALOPERIDOL AND HALOPERIDOL - EVALUATION OF POSSIBLE MECHANISMS

In patients taking haloperidol (HP), circulating concentrations of red uced haloperidol (RHP increase disproportionately to the dose or conce ntration of the parent drug. In the current study, we tested the hypot hesis that the nonlinearity is due to preferential saturation of the r eoxidation of RHP to HP, and two factors that could amplify the nonlin earity - concentration-dependent binding of RHP by plasma proteins, or by red blood cells. In 25 patients with schizophrenia who were taking HP, the unbound fraction of HP (0.085 +/- 0.016) and RHP (0.244 +/- 0 .026) in plasma, and the blood:plasma ratio for each compound were ind ependent of their concentration. Thus, saturable binding of RHP to pla sma proteins or red blood cells can be excluded. HP reductase and RHP oxidase activity were measured in human liver cytosol and microsomal f ractions, respectively. Because ketone reductase-catalysed formation o f RHP is stereospecific, we examined each enantiomer of RHP separately . The V-max for the oxidation of the S(-) and R(+) RHP enantiomers in four livers was 0.23 +/- 0.15 and 0.60 +/- 0.32 mu mol/g protein per m in (mean +/- SD), respectively The K-m was 110 +/- 40 and 70 +/- 10 mu M, respectively. In contrast, HP reductase activity displayed greater capacity and was not saturable. The rate of production of RHP at a HP concentration of 122 mu M (the limit of HP solubility) in the same li vers was 2.6 +/- 0.7 mu mol/g protein per min. Despite the observed no nlinearity between the enzymatic pathways in vitro, RHP concentrations in vivo are 2-3 orders of magnitude lower than the K-m for oxidation of each enantiomer of RHP. Thus, it is unlikely that either saturable oxidation of RHP to HP, or saturable plasma protein or red cell bindin g account for the nonlinear relationship between steady state concentr ations of RHP and HP in vivo.