CORRELATION OF (-)N(6)-PHENYLISOPROPYLADENOSINE BLOOD-LEVELS WITH CARDIAC RESPONSES IN THE ANESTHETIZED GUINEA-PIG

This study was designed to develop a high-performance liquid chromatog raphy-based analytical method to measure the blood concentration of (- )N6-phenylisopropyladenosine (R-PIA) in order to correlate such levels with cardiac responses, and to determine the pharmacokinetics of R-PI A. Experiments were carried out in anesthetized adult guinea pigs inst rumented for measurement of the surface ECG. After i.v. (50 mug/kg; n = 9) or i.p. (3.5 mg/kg; n = 5) administration of R-PIA, the atrial ra te and P-R interval were determined, and arterial blood samples (0.5 m l) were collected. The R-PIA content of plasma ultrafiltrates was dete rmined by reversed-phase high-performance liquid chromatography. The r atio of R-PIA concentrations in whole blood and in ultrafiltrated plas ma (free or unbound) at 35-37-degrees-C was 2.51 +/- 0.10 (n = 7) and was relatively independent of R-PIA concentration. The concentration o f unbound R-PIA in whole blood correlated well with cardiac responses. Two distinct patterns of cardiac response to varying R-PIA levels wer e observed. In 4 of 14 animals, R-PIA caused a prolongation of the P-R interval at a relatively constant atrial rate, whereas in 10 animals, R-PIA caused both a slowing of atrial rate and a prolongation of the P-R interval. An increase in the unbound concentration of R-PIA caused a decrease in atrial rate and an increase in P-R interval. Unbound R- PIA was rapidly cleared from blood (CL = 40 +/- 7 ml/kg/min) and had a large volume of distribution (V(ss) = 1.45 +/- 0.21 L/kg). Additional pharmacokinetic analysis indicated that the use of R-PIA as a pharmac ologic tool would be improved by using a continuous infusion to achiev e steady-state plasma levels rather than intermittent injections that provide widely fluctuating concentrations.