IN-VIVO RECEPTOR OCCUPANCY OF THE ANGIOTENSIN-II RECEPTOR BY NONPEPTIDE ANTAGONISTS - RELATIONSHIP TO IN-VITRO AFFINITIES AND IN-VIVO PHARMACOLOGICAL POTENCY

The affinities of 13 angiotensin II antagonists for the AT(1) subtype determined in vitro with tissue homogenates were shown not to correlat e well with in vivo pharmacologic potency. The addition of human serum albumin to the in vitro assay to mimic in vivo plasma protein interac tions reduced the measured affinity by reducing the effective free con centrations of antagonists, but the resulting affinities were not pred ictive of the in vivo effects. Using an in vivo radioligand competitio n assay, in which receptor occupancy is demonstrated via competitive b lockade of the in vivo binding of [I-125][Sar(1),Ile(8)]angiotensin II to AT(1) receptors in rat kidney cortex, we demonstrated that the in vivo pharmacologic potencies reflect receptor occupancy. By comparing the effects of rat plasma and bovine serum albumin on the in vitro aff inity of two antagonists, we suggest that the use of plasma would alte r free plasma concentrations in a manner more consistent with in vivo measures of potencies.