Human Plasma Protein Binding of the Angiotensin II Receptor Antagonist Losartan Potassium (DuP 753/MK 954) and Its Pharmacologically Active Metabolite EXP3174

The in vitro protein binding characteristics of the prototypical angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174 were determined by ultrafiltration ivith plasma from naive donors, volunteers dosed with losartan, and purified human plasma proteins. The binding of losartan was high, with a percent unbound (free) of 1.4 ± 0.2% to 1.2 ± 0.1% at concentrations ranging from 0.5 to 5.0 μg/mL; that ist approximately 98.6 to 98.8% bound. EXP3174 was more highly bound than losartan (P < .05) ivith 0.2 ± 0.0% free at concentrations ranging from 0.1 to 10.0 μg/mL; or, greater than 99.7% bound. The binding in the plasma from volunteers given oral losartan was similar to that determined with plasma from naive donors, with 1.5 ± 0.3 versus 1.4 ± 0.1% free for losartan, and 0.5 ±0.1 versus 0.4 ± 0.0% for EXP3174, respectively. This extensive plasma binding of both acidic compounds occurs primarily to albumin, with negligible binding to the α1‐acid glycoprotein. Although highly bound, neither losartan nor EXP3174 were displaced in vitro by pharmacologically relevant concentrations of non‐steroidal antiinflammatory drugs (NSAlDs), warfarin, or diazepam; however, suprapharmacologic concentrations of the NSAIDs increased the free fraction of both compounds. These data show that the angiotensin II receptor antagonists losartan and EXP3174 are highly bound to plasma albumin in humans, although clinically significant drug interactions due to displacement from binding sites are unlikely. Moreover, these data may be used to estimate the unbound plasma concentrations in published and subsequent pharmacokinetic studies, an important parameter because it is generally recognized that only the unbound drug is available for distribution into tissues and binding to receptors.