Specific binding of [3H]-irbesartan to human AT1-receptors in CHO cells was saturable with a KD of 1.94 +/- 0.12 and a dissociation half-life of approximately seven minutes at 37 degrees C.
The binding kinetics of irbesartan to human AT1 receptors show a dissociation half-life of ~7 minutes, which explains its partially insurmountable inhibition but indicates that sustained in vivo antihypertensive effects depend on other pharmacokinetic factors.
The aim of the present work was to investigate the binding properties of the selective AT(1)-receptor antagonist irbesartan to human AT(1)-receptors by direct radioligand binding. For this purpose the specific binding of (3)H-irbesartan to intact Chinese Hamster Ovary (CHO) cells expressing human recombinant AT(1)-receptors was determined. Specific binding of (3)H-irbesartan rapidly reached equilibrium and was saturable with a KD of 1.94 +/- 0.12 to a homogeneous class of binding sites. Its binding was inhibited by other AT(1) antagonists (AIIAs) with the same potency order as previous results from (3)H-angiotensin II and (3)H-candesartan binding to human AT(1)-receptors. Whereas the dissociation rate of (3)H-irbesartan was essentially independent of the radioligand concentration, it was much slower at 12 degrees C when compared with 37 degrees C. Moreover, the dissociation rate was similar, as determined in washout experiments in the absence or presence of unlabelled AT(1) antagonists. At 37 degrees C the dissociation rate constant corresponded to a half-life of approximately seven minutes, which is sufficient to explain the partially insurmountable inhibition by irbesartan in previous studies. In contrast, other phenomena such as the plasma half life and tissue-related factors are necessary to explain its sustained in vivo antihypertensive effect.
Vanderheyden et al. (Thu,) reported a other. [3H]-irbesartan was evaluated on Binding properties (KD and dissociation rate). Specific binding of [3H]-irbesartan to human AT1-receptors in CHO cells was saturable with a KD of 1.94 +/- 0.12 and a dissociation half-life of approximately seven minutes at 37 degrees C.
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