Pharmacokinetics of chlorpromazine-induced miotic response in rabbits

The time variation of changes in the chlorpromazine-induced pupil diameter decrease was studied following varying bolus and slowly infused intravenous doses administered to rabbits. The observed pharmacological response data were coverted, via, the use of a dose-effect curve, to values theoretically corresponding to relative biophasic drug levels. These values were, in turn, used to construct a linear pharmacokinetic model of the drug bioavailability input equilibrium pharmacological response output dynamics of the system. The use of a time domain, MULTIFIT, computerized method of fitting the data to obtain a pharmacokinetic model was compared to the use of a frequency response, PLTEST, approach. The fidelity of the model in quantitatively relating the time course of systemic drug bioavailability to observed pupil response was verified by the satisfactory agreement obtained by directly comparing experimentally known amounts of drug intravenously infused with corresponding values computed from observed changes in pupil size. The applicability of using pharmacological data for quantitative bioavailability and pharmacokinetic analysis of chlorpromazine is demonstrated. This finding is particularly significant because no suitable chemical or radiological direct assay technique exists for determining levels of chlorpromazine, except for high doses, in body fluids.