Nonlinear relationship between circulating concentrations of reduced haloperidol and haloperidol: evaluation of possible mechanisms

Abstract

In patients taking haloperidol (HP), circulating concentrations of reduced haloperidol (RHP increase disproportionately to the dose or concentration of the parent drug. In the current study, we tested the hypothesis that the nonlinearity is due to preferential saturation of the reoxidation of RHP to HP, and two factors that could amplify the nonlinearity — 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 independent of their concentration. Thus, saturable binding of RHP to plasma proteins or red blood cells can be excluded. HP reductase and RHP oxidase activity were measured in human liver cytosol and microsomal fractions, respectively. Because ketone reductase-catalysed formation of RHP is stereospecific, we examined each enantiomer of RHP separately. The V_max for the oxidation of theS(−) andR(+) RHP enantiomers in four livers was 0.23±0.15 and 0.60±0.32 µmol/g protein per min (mean ± SD), respectively The K _m was 110±40 and 70±10 µM, 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 µM (the limit of HP solubility) in the same livers was 2.6±0.7 µmol/g protein per min. Despite the observed nonlinearity 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 binding account for the nonlinear relationship between steady state concentrations of RHP and HP in vivo.