A Retrospective Analysis of Human Angiotensin II Receptor Blockers (ARB) Pharmacokinetics, Dosages and <i>C</i> _max Values for the Experimental Modelling of Pleiotropic and Supratherapeutic Activities

Angiotensin II (AngII) receptor blockers (ARBs) are medications that lower systolic blood pressure (BP) by antagonizing the AngII type 1 receptor (AT1). However, ARBs have documented or suspected therapeutic properties in diseases not caused by high BP including diabetes, muscular dystrophy, chronic obstructive pulmonary diseases (COPD) and Alzheimer's disease. ARBs have multiple pleiotropic properties; 'on-target' AT1-dependent pleiotropy can arise from blocking AngII-AT1 binding in non-BP-regulating cells or via inverse or biased ARB-AT1 agonism. In addition, activation of cells lacking AT1 by ARBs suggests the presence of AT1-independent 'off-target' pleiotropy, whereas supratherapeutic properties in the absence of further BP lowering have also been reported. Herein, to determine how ARB pleiotropy and supratherapeutic properties can be modelled in vitro or ex vivo, we perform a retrospective analysis of the literature that characterizes their maximal human plasma concentration, C_max, which is higher and more likely to trigger pleiotropy than their low nanomolar, AT1-blocking concentrations. Our findings suggest that C_max is variable and heterogeneous between ARBs, with upper range values as high as 13.6 micromolar in the case of valsartan and lower range values as low as 0.4 micromolar for candesartan. We propose that modelling of ARB pleiotropy be conducted at these concentrations, whereas higher concentrations will mimic supratherapeutic applications.