Concentration-response relations for apomorphine effects on heart rate in conscious rats

Abstract

Abstract The pharmacokinetics of apomorphine in plasma and brain tissue have been studied in relation to the time courses of effects on heart rate in conscious rats. The kinetic behaviour was investigated after 2 mg kg−1 i.v. and 5 mg kg−1 s.c., respectively. Apomorphine showed a high total plasma clearance (165–207 ml min−1 kg−1) and, despite a relatively large volume of distribution (3.4–4.1 litre kg−1), a biological half-life of about 14 min was obtained irrespective of route of administration. The kinetics in whole brain were identical with those in plasma. Apomorphine produced biphasic effects on the heart rate during the time courses of subcutaneous single doses: a low dose (50 μg kg−1) induced pure bradycardia while the doses of 100 μg kg−1 and 5 mg kg−1 produced responses oscillating between bradycardia and tachycardia. When we evaluated the relation between apomorphine concentrations and effects on the heart frequency with a composed sigmoid Emax model, apomorphine exhibited a U-shaped steady-state plasma concentration-response curve. Bradycardia appeared after low concentrations, reached a maximum and then decreased with increasing concentrations. A further augmentation of apomorphine concentration resulted in the opposite effect, i.e. tachycardia. Separate concentration-response curves for bradycardia and tachycardia were calculated. The changes in biophase concentration that occur during the absorption and disposition may thus cause the fluctuations between contrasting effects seen during the time course of a single dose.