armful effects elicited by Agtr1 are counterbalanced by the Agtr2 mediated signaling. This pathway promotes vasodilation, NO release and growth inhibition. The Agtr1 mediated pathway is the better understood one. Losartan is one of eight Agrt1 antagonists collectively known as ARBs that are clinically available; losartan is the first marketed and the most frequently prescribed. ARBs are effective antihypertensive agents; however, they exhibit differences in terms of pharmacokinetics properties and pleiotropic effects. The losartan parent compound has a rather moderate affinity for the receptor. Following rapid absorption, losartan is metabolized to the more potent metabolite E3174 via the E3179 intermediate. The affinity of E3174 for the Agtr1 is 20- to 30-times greater than that of losartan. Other minor metabolites are also produced that are less active than the parent compound. In humans, the main cytochrome P450 enzymes involved in losartan phase I biotransformation are CYP3A4 and CYP2C9 with CYP2C8 also contributing. The phase II biotransformation (glucuronidation) is carried out by the UGT1A1 and UGT2B7 enzymes. The ABCB1 member is involved in the efflux of losartan and metabolites. The Agtr1 receptor is a G-protein coupled receptor (GPCR) that couples to the Galphaq of heterotrimeric G proteins that activates phospholipase C; subsequent events lead to the activation of the protein kinase C (PKC) intracellular pathway. In the context of Agtr1, transactivation of epidermal growth factor/neuregulin and of Erk1/2 signaling as well as activation of the Jak-Stat pathway have been reported. The allelic variants of CYP2C9, depending on the identity of the variant, exhibit decreased formation of E3174 or seem to not affect the antihypertensive response. However, further investigations of this and other enzymes in the losartan pharmacokinetics pathway are necessary in order the assess the effect(s) of genetic variation on the therapeutic efficacy of the drug. Several amino acids have been identified as candidate components of the binding pocket of Agtr1. For losartan and probably E3174, these are serine 109, lysine 199 to a lesser extent, and asparagine 295 within transmembrane (TM) domains 3, 5 and 7 of the human receptor, respectively. These amino acids are conserved in the rat and mouse genes. In the model of the human receptor bound to its natural agonist, these positions are close to some of the positions the ligand uses and one position is identical. Given that the affinity of losartan (and other ARBs) matches the affinity of AngII, it is conceivable that the binding of antagonists interferes with the binding of the natural ligand. Losartan, in addition to its antihypertensive effects, may also slow down the progression of diabetic nephropathy, reduce renal disease progression in patients with type 2 diabetes (T2D) and decrease peripheral insulin resistance in T2D patients and animal models. Losartan also exhibits uricosuric action, possibly via inhibition of urate transporter 1, Slc22a12 known as URAT1 - one of several apical urate/anion exchangers involved in the reabsorption of urate in the proximal tubules. While some adverse side effects of ARBs have been reported, they are relatively rare....(less)