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

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.(ABSTRACT TRUNCATED AT 250 WORDS)