Altered pharmacokinetics and dynamics of apomorphine in the malnourished rat: modeling of the composed relationship between concentration and heart-rate response

Abstract

The impact of malnutrition on the pharmacokinetics and pharmacodynamics (change in heart rate) of apomorphine was studied in the rat. One group of rats received a low-protein diet (0.5%) ad libitum to produce prekwashiorkor. The control group received commercial food pellets. In the first experiment, the two groups received a 2 mg/kg iv bolus dose of apomorphine to determine any differences in the basic pharmacokinetic parameters. The pharmacodynamic characteristics in each group were studied at different steady-state plasma levels, achieved by iv infusions with continuous measurements of the heart rate. There was an almost twofold decrease in the plasma clearance in the malnourished rats compared with controls. A pronounced change in the pharmacodynamic response was also observed in the malnourished group. In the control group, apomorphine produced bradycardia at low concentrations and tachycardia at high concentrations, while only bradycardia was registered in the malnourished group, with maximum effects at steady-state plasma concentrations of 50 ng/ml and a return to baseline at higher concentrations. The effects in control and malnourished rats were fitted simultaneously to the sum of two Hill equations with a nonlinear regression program, and the fits were compared by means of an F test. The maximum pure tachycardia obtainable differed significantly in the prekwashiorkor group compared to the control group. These results suggest a selective down regulation/desensitization only of the receptors responsible for the tachycardia produced by apomorphine during malnutrition.