AIRWAY DEPOSITION AND CLEARANCE AND SYSTEMIC PHARMACOKINETICS OF AMILORIDE FOLLOWING AEROSOLIZATION WITH AN ULTRASONIC NEBULIZER TO NORMAL AIRWAY

Study objectives: Airway epithelial ion transport is an important comp onent of the airway defense mechanism, and new therapies that target i on transport are being developed, Amiloride is an example of such a ne w drug, exerting a dose-dependent action to inhibit Na+ transport. Ami loride may be useful in cystic fibrosis, blocking the characteristic a irway epithelial Na+ hyperabsorption that occurs in the disease, To ev aluate airway and systemic delivery of amiloride via an ultrasonic neb ulizer (Omron NE-UO7), we measured the airway surface concentrations o f amiloride in normal volunteers via a novel approach, together with t he systemic pharmacokinetics of amiloride. Design: Direct measurement of airway surface liquid, plasma, and urine amiloride concentrations f ollowing ultrasonic nebulization. Participants/interventions: Seven no rmal subjects were studied in the General Clinical Research Center of the University of North Carolina, Following inhalation with amiloride (1 mg/mL, 4.5 mt) for approximately 12 min, a bronchoscopy was perform ed, Amiloride deposition and clearance from airway surfaces over 1 h w ere evaluated by transbronchoscopic sampling using preweighed filter p apers, Pulmonary and systemic absorption was assessed by measuring dru g concentrations in blood and urine, Results: The mean volume aerosoli zed was 3.5+/-0.3 mt during 12 min of aerosolization time; the mean in itial concentration of amiloride on airway surfaces after nebulization was 1.6x10(-4) mol/L, with an elimination half life of approximately 23 min, Peak plasma concentrations of amiloride (30 min, 3.36+/-0.70 n g/mL) suggest early absorption across lung surfaces, rather than via t he GI route. Mean urinary excretion of amiloride over 72 h was 0.63+/- 0.07 mg, with 87% excreted in the first 24 h, Conclusions: The ultraso nic nebulizer rapidly delivers amiloride to normal conducting airways as assessed by the transbronchoscopic sampling technique. Early blood concentrations of amiloride probably reflect initial absorption across lung surfaces and are a useful index of the efficiency of die machine .