Losartan Metabolite EXP3179

Abstract

Losartan potassium, the first orally active nonpeptide angiotensin receptor blocker (ARB) to be introduced for clinical use in hypertension, is rapidly absorbed after oral administration, reaching a peak in plasma 1 to 2 hours. Despite being metabolized by the cytochrome P450 (CYP) 3A4, 2C9, and 2C10 isoenzymes, losartan has no clinically relevant interactions with inhibitors and stimulators of the CYP450 system and, like the other ARBs, is devoid of significant adverse effects: hypotension-related dizziness was the only drug-related event reported more frequently with losartan monotherapy than with placebo in clinical trials.1 After oral administration about 14% of a losartan dose is converted to the EXP3174 metabolite, which is 10- to 40-fold more potent than losartan and mediates most of its angiotensin type 1 receptor (AT1-R)–blocking effects. Losartan was generally deemed to be devoid of agonistic properties,2 but an important intermediate aldehyde metabolite EXP3179 has been identified (Figure).3 EXP3179 has no AT1-R–blocking activity, but potently inhibits the expression of endothelial cyclooxygenase (COX)-2, thereby exerting potent antiinflammatory actions. It also blocked intercellular adhesion molecule (ICAM)-1 mRNA upregulation and COX-dependent thromboxane A2 and prostaglandine F2α generation in vitro. Moreover, EXP3179 stimulated the phosphorylation of the endothelial nitric oxide synthase through a PI3-kinase/Akt pathway downstream of the VEGF-receptor 2 in cultured endothelial cells.4 As the ligand-activated PPAR-γ also exerts antiinflammatory actions (by inhibiting the action of proinflammatory transcription factors, such as AP-1 and nuclear factor kB), and represses COX-2 promoter activity and mRNA expression (by interacting with the c-jun component of the AP-1 complex), in this issue of Hypertension Kappert et al investigated the hypothesis that EXP3179-mediated activation of PPAR-γ entails a novel mechanism of the antiinflammatory antidiabetic actions of losartan.5 Figure. Schematic representation of losartan metabolism via cytochrome P450. See text for explanation. PPAR-γ is a nuclear …