A Pharmacodynamic Model to Predict the Time Dependent Adaptation of Dopaminergic Activity During Constant Concentrations of Haloperidol

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Abstract
The concentration-response relationship of the accumulation of brain homovanillic acid (HVA) has been studied by giving rats a shorter (12 h) and a longer (76 h) constant intravenous infusion of haloperidol, respectively, at rates aiming at different steady state blood concentrations of haloperidol of 5 to 30 ng mL−1. The observed response on brain HVA concentration vs increasing steady state blood concentration of the drug produced a bell-shaped type of curve during the 12 h infusion. When the infusion proceeded for 76 h a similar type of curve was obtained but it was shifted downwards compared with the 12 h infusion. The dopaminergic activity of the rat brain, as reflected by the HVA levels, therefore adapted to a lower activity during the prolonged exposure to haloperidol. To follow the time course of this adaptation, one steady state level of about 12 ng mL−1 was established and kept for 12, 28, 52 and 76 h. The result showed that the accumulation of brain HVA decreased over time compared with control animals given placebo. A pharmacodynamic model was set up to quantitatively describe the time-dependent adaptation of HVA accumulation in the whole rat brain during constant haloperidol administration. By fitting this model to all three sets of experimental data simultaneously, an adaptation half-time of about 38 h ± 14(s.d.) and a tolerance potency of about 7 ng mL−1 were obtained which could be used to calculate that, for example, at a constant blood level of 10 ng mL−1 haloperidol over 5 days the accumulation of brain HVA decreased by approximately 91% of the maximal decrease. Since the therapeutic effects of haloperidol take time to become apparent, the adaptation of HVA-accumulation seen in the present experiments and in the clinical literature could be related to the drug's antipsychotic effect. The adaptation half-time could be a useful parameter to describe and predict the rate of development of the desired therapeutic effect. Furthermore. the observed bell-shaped effect of increasing steady state blood concentrations of haloperidol on the accumulation of brain HVA corresponded to the clinically observed therapeutic haloperidol plasma concentrations of patients with schizophrenia.