Disposition of quinapril and quinaprilat in the isolated perfused rat kidney

Abstract

An isolated perfused rat kidney model was used to probe the renal disposition of quinapril and quinaprilat after separate administration of each drug species. Control studies were performed with drug-free perfusate (n = 8) and perfusate containing quinapril (n = 9) or quinaprilat (n = 7) at initial drug concentrations of 1000 ng/ml (including corresponding tracer levels of tritiated drug). Physiologic parameters were within the normal range of values for this technique and were stable for the duration of each experiment. Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a specific and sensitive reversed-phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. Perfusate protein binding was determined using an ultrafiltration method at 37 degrees C. The total renal clearance of quinapril (CLr) was calculated as Dose/AUC(0-infinity), and is represented by the sum of its urinary and metabolic clearances. The urinary clearances (CLe) of quinapril and quinaprilat were calculated as urinary excretion rate divided by midpoint perfusate concentration for each respective species. Of the total renal clearance for quinapril (CLr = 4.49 ml/min), less than 0.1% was cleared as unchanged drug (CLe = 0.004 ml/min); over 99% of the drug was cleared as quinaprilat formed in the kidney. The clearance ratio of quinapril [CR = CLr/(fu.GFR)] was 41.0, a value representing extensive tubular secretion into the renal cells. Following quinaprilat administration, the clearance ratio of metabolite [CR = CLe/(fu.GFR)] was 3.85, indicating a net secretion process for renal elimination.