Effects of short IV infusions of DT-009, a novel adenosine (A?) receptor agonist, on renal function in healthy subjects

Abstract

Purpose To study the renal effects of DT-009, a selective A1-receptor agonist currently in phase II clinical testing for ventricular rate control in atrial fibrillation. Methods Ten healthy young volunteers (age: 21–35) received a 30-minute infusion of 1μg/kg, 5μg/kg of DT-009 or saline on three different occasions. The subjects were hydrated by saline infusion (200 ml/min) for one hour prior to and five hours after the start of study drug infusion. Serial plasma and urine samples were taken over 24 hours to measure creatinine, Na and K by validated methods. The following renal function markers were assessed over time: urinary flow rate (UF), creatinine clearance (CLCrea), Na and K clearance (CLNa and CLK). Results Initially, DT-009 transiently reduced diuresis, natriuresis and kaliuresis due to a significant, dose-dependent inhibition of CLCrea, CLNa and to a lesser extent CLK. The inhibitory effects on CLCrea were shorter (1–2 hours) than the effects on CLNa (3–4 hours). Dose-dependent secondary effects (rebounds) in UF and natriuresis were apparent after 5–10 hours. Conclusions DT-009 transiently reduces glomerular filtration, presumably by renal vasoconstriction, as well as tubular reabsorption via activation of renal A1-receptors. Counter-regulatory mechanisms seem to blunt these primary effects. Clinical Pharmacology & Therapeutics (2005) 77, P58–P58; doi: 10.1016/j.clpt.2004.12.112