Tubular transport mechanisms of quinapril and quinaprilat in the isolated perfused rat kidney: effect of organic anions and cations.
The clearance mechanisms of quinapril and quinaprilat were probed using an isolated perfused rat kidney model. Sixty-four experiments were performed with drug in the absence and presence of classic inhibitors of the organic acid (i.e., probenecid and p-aminohippurate) and organic base (i.e., tetraethylammonium and quinine) transport systems of the proximal tubule. Initial perfusate concentrations of quinapril and quinaprilat were approximately 2.36 microM (or 1000 ng/ml), and transport inhibitors were coperfused at 100-10,000 times the drugs' initial microM concentrations. Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a 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. Overall, the clearance ratios of quinapril (total renal clearance divided by fu x GFR) and quinaprilat (urinary clearance divided by fu. GFR) were significantly reduced, and in a dose-dependent manner, by the coperfusion of organic acids but not organic bases. The data demonstrate that the organic anionic secretory system is the primary mechanism by which quinapril and quinaprilat are transported into and across renal proximal cells.
Kugler
A R
AR
Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106-1047, USA.
Olson
S C
SC
Smith
D E
DE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000493:pharmacokinetics*; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011485:Protein Binding; D000077583:Quinapril; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C054501:quinaprilat; D000077583:Quinapril