Abstract
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 μM (or 1000 ng/ml), and transport inhibitors were coperfused at 100–10,000 times the drugs' initial μM 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°C. Overall, the clearance ratios of quinapril (total renal clearance divided byfu·GFR) and quinaprilat (urinary clearance divided byfu·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.
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J. B. Kostis, J. J. Raia, Jr., E. A. DeFelice, J. A. Barone, and R. G. Deeter. Comparative clinical pharmacology of ACE inhibitors. In J. B. Kostis and E. A. DeFelice (eds.),Angiotensin Converting Enzyme Inhibitors, Alan R. Liss, New York, 1987 pp. 19–54.
R. N. Brogden, P. A. Todd, and E. M. Sorkin. Captopril: An update of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure.Drugs 36:540–600 (1988).
P. A. Todd and K. L. Goa. Enalapril: A reappraisal of its pharmacology and therapeutic use in hypertension.Drugs 43:346–381 (1992).
A. N. Wadworth and R. N. Brogden. Quinapril: A review of its pharmacological properties, and therapeutic efficacy in cardiovascular disorders.Drugs 41:378–399 (1991).
G. H. Williams and E. Braunwald. Hypertensive vascular disease. In E. Braunwald, K. J. Isselbacher, R. G. Petersdorf, J. D. Wilson, J. B. Martin, and A. S. Fauci (eds.),Harrison's Principles of Internal Medicine, 11th ed., McGraw-Hill, New York, 1987, pp. 1024–1037.
A. R. Kugler, S. C. Olson, and D. E. Smith. Disposition of quinapril and quinaprilat in the isolated perfused rat kidney.J. Pharmacokin. Biopharm. 23:287–305 (1995).
J. M. Nishiitsutsuji-Uwo, B. D. Ross, and H. A. Krebs. Metabolic activities of the isolated perfused rat kidney.Biochem. J. 103:852–862 (1967).
R. H. Bowman. The perfused rat kidney.Meth. Enzymol. 39:3–11 (1975).
F. H. Epstein, J. T. Brosnan, J. D. Tange, and B. D. Ross. Improved function with amino acids in the isolated perfused kidney.Am. J. Physiol. 243:F284-F292 (1982).
H. A. Krebs and K. Henseleit. Untersunchugen uber die harnstoffbildung im tierkorper.Z. Physiol. Chem. 210:33–36 (1932).
A. R. Kugler, S. C. Olson, and D. E. Smith. Determination of quinapril and quinaprilat by high-performance liquid chromatography with radiochemical detection, coupled to liquid scintillation spectrometry.J. Chromatog. B. 666:360–367 (1995).
T. Prueksaritanont, M. L. Chen, and W. L. Chiou. Simple and micro high-performance liquid chromatographic method for simultaneous determination of p-aminohippuric acid and iothalamate in biological fluids.J. Chromatog. 306:89–97 (1984).
B. D. Ross. The isolated perfused rat kidney.Clin. Sci. Mol. Med. 55:513–521 (1978).
T. Maack. Physiological evaluation of the isolated perfused rat kidney.Am. J. Physiol. 238:F71-F78 (1980).
I. Bekersky. Use of the isolated perfused kidney as a tool in drug disposition studies.Drug Metab. Rev. 14:931–960 (1983).
C. A. Rodríguez and D. E. Smith. Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys.Antimicrob. Agents Chemother. 35:2395–2400 (1991).
C. A. Rodríguez and D. E. Smith. Influence of angiotensin II-induced alterations in renal flow on excretion of cefonicid in isolated perfused rat kidneys.Antimicrob. Agents Chemother. 36:616–619 (1992).
D. E. Smith, S. Guillard, and C. A. Rodríguez. Effect of angiotensin II-induced changes in perfusion flow rate on chlorothiazide transport in the isolated perfused rat kidney.J. Pharmacokin. Biopharm. 20:195–207 (1992).
A. R. Kugler, S. C. Olson, and R. A. Jordan. In vitro quinapril metabolism in rat, dog, monkey, and human liver preparations.Pharm. Res. 8(Suppl.):S-239 (1991).
H. R. Kaplan, D. G. Taylor, S. C. Olson, and L. K. Andrews. Quinapril: A preclinical review of the pharmacology, pharmacokinetics, and toxicology.Angiology 40:335–350 (1989).
J. H. Lin, I. W. Chen, E. H. Ulm, and D. E. Duggan. Differential renal handling of angiotensin-converting enzyme inhibitors enalaprilat and lisinopril in rats.Drug Metab. Dispos. 16:392–396 (1988).
I. A. M. de Lannoy, R. Nespeca, and K. S. Pang. Renal handling of enalapril and enalaprilat: Studies in the isolated red blood cell-perfused rat kidney.J. Pharmacol. Exp. Ther. 251:1211–1222 (1989).
D. E. Smith and A. R. Kugler. Influence of intrarenal metabolism on the analysis of renal drug transport mechanisms.J. Pharm. Sci. 88:1519–20 (1994).
S. K. Mujais, A. Quintanilla, M. Zahid, K. Koch, W. Shaw, and T. Gibson. Renal handling of enalaprilat.Am. J. Kidney Dis. 19:121–125 (1992).
S. C. Olson, A. M. Horvath, B. M. Michniewicz, A. J. Sedman, W. A. Colburn, and P. G. Welling. The clinical pharmacokinetics of quinapril.Angiology 40:351–359 (1989).
S. M. Singhvi, K. L. Duchin, D. a. Willard, D. N. McKinstry, and B. H. Migdalof. Renal handling of captopril: Effect of probenecid.Clin. Pharmacol. Ther. 32:182–189 (1982).
F. H. Noormohamed, W. R. McNabb, and A. F. Lant. Pharmacokinetic and pharmacodynamic actions of enalapril in humans: Effect of probenecid pretreatment.J. Pharmacol. Exp. Ther. 253:362–368 (1990).
K. Weisser, J. Schloos, S. Jakob, W. Mühlberg, D. Platt, and E. Mutschler. The influence of hydrochlorothiazide on the pharmacokinetics of enalapril in elderly patients.Eur. J. Clin. Pharmacol. 43:173–177 (1992).
K. L. Duchin, D. N. McKinstry, A. I. Cohen, and B. H. Migdalof. Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases.Clin. Pharmacokin. 14:241–259 (1988).
V. Vertes and R. Haynie. Comparative pharmacokinetics of captopril, enalapril, and quinapril.Am. J. Cardiol. 69:8C-16C (1992).
V. Ganapathy, M. Brandsch, and F. H. Leibach. Intestinal transport of amino acids and peptides. In L. R. Johnson (ed.),Physiology of the Gastrointestinal Tract, Raven Press, New York, 1994, pp. 1773–1794.
G. L. Amidon and H. J. Lee. Absorption of peptide and peptidomimetic drugs.Ann. Rev. Pharmacol. Toxicol. 34:321–341 (1994).
D. E. Smith, A. R. Kugler, and J. B. Schnermann. Reabsorption and metabolism of quinapril and quinaprilat in rat kidney: In vivo micropuncture studies.J. Pharm. Sci. 84:1147–1150 (1995).
D. C. Brater, P. P. Sokol, S. D. Hall, and T. D. McKinney. Disposition and dose requirements of drugs in renal insufficiency. In D. W. Seldin and G. Giebisch (eds.),The Kidney Physiology and Pathophysiology, 2nd ed., Raven Press, New York, 1992, pp. 3671–3695.
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This work was supported in part by a gift from Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company and by National Institutes of Health Grant R01 GM35498.
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Kugler, A.R., Olson, S.C. & Smith, D.E. Tubular transport mechanisms of quinapril and quinaprilat in the isolated perfused rat kidney: Effect of organic anions and cations. Journal of Pharmacokinetics and Biopharmaceutics 24, 349–368 (1996). https://doi.org/10.1007/BF02353517
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DOI: https://doi.org/10.1007/BF02353517