Effect of altered AGP plasma binding on heart rate changes by S(-)-propranolol in rats using mechanism-based estimations of in vivo receptor affinity (K(B,vivo))

Abstract

In contrast to the impact of plasma protein binding on pharmacokinetics, no quantitative in vivo information is available on its impact on pharmacodynamics. The pharmacokinetic-pharmacodynamic relationship of the model drug S(-)-propranolol was evaluated using mechanism-based estimations of in vivo receptor affinity (K(B,vivo)), under conditions of altered plasma protein binding resulting from different levels of alpha-1-acid glycoprotein (AGP). Male Wistar Kyoto rats with isoprenaline-induced tachycardia received an intravenous infusion of S(-)-propranolol, on postsurgery day 2 (n = 7) and day 7 (n = 8) with elevated and normal plasma protein binding, respectively. Serial blood samples were taken in parallel to heart rate measurements. AGP concentrations at 2 and 7 days postsurgery were 708 +/- 274 and 176 +/- 111 microg/mL (mean +/- SE), respectively. Using nonlinear mixed effects modeling, AGP concentration was a covariate for intercompartmental clearance for the third compartment of the pharmacokinetic model of S(-)-propranolol. Individual values of AGP concentrations ranged between 110 and 1150 microg/mL, and were associated with K(B,vivo) values of S(-)-propranolol from 7.0 to 30 nM. Using the K(B,vivo) for S(-)-propranolol with correction for average values for normal and elevated plasma protein binding, nearly identical values were found. This confirms, strictly quantitative, earlier indications that plasma protein binding restricts the pharmacodynamics of S(-)-propranolol.