The kidney plays a major role in the elimination of drugs. The purpose of this paper is to: (i) review the mechanisms of renal elimination; (ii) identify potential mechanisms for renal drug interactions; (iii) review in vitro and in vitro animal models for studying renal elimination mechanisms and identifying potential drug-drug interactions; (iv) review experimental designs used in identifying drug-drug interactions in humans with an emphasis on gaining information regarding the mechanism of the interaction; and (v) make recommendations regarding the potential for renal drug interactions in drug development.
It is concluded that clinically significant drug interactions resulting in toxicity because of some mechanism at the renal level appear to be relatively rare and that in vitro screening should not be done on all drugs during drug development. Five potential mechanisms exist for drug interactions at the renal level: (i) a displacement of bound drug resulting in an increase in drug excretion via an increase in glomerular filtration; (ii) competition at a tubular secretion site resulting in a decrease in drug excretion; (iii) competition at the tubular reabsorption site resulting in an increase in drug excretion; (iv) a change in urinary pH and/or flow that may increase or decrease drug excretion depending on the pKa of the drug; and (v) inhibition of renal drug metabolism.
The most well known renal drug interaction is competitive inhibition of tubular secretion, ultimately leading to an increase in plasma drug concentration. Only when renal clearance is a major contributor to the total clearance (>30%) and plasma concentrations are greater than the Michaelis-Menten transport constant does the potential exist for clinically significant renal drug-drug interactions because only then does nonlinear pharmacokinetics become evident. The potential for drug interactions is small when renal clearance is less than 20 to 30% of the total clearance and/or when plasma concentrations are less than the Michaelis-Menten transport constant, unless the drug has a narrow therapeutic window.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Vander AJ, Sherman JH, Luciano DS. Human physiology. New York: McGraw-Hill, 1990.
Narayanan S. Renal biochemistry and physiology: pathophysiology and analytical perspectives. Adv Clin Chem. 1992; 29: 121–59.
Vickers AEM, Fischer V, Connors MS, et al. Biotransformation of the antiemetic 5-HT3 antagonist tropisetron in liver and kidney slices of human, rat, and dog with a comparison to in vivo. Eur J Drug Metab Pharmacokinet. 1996; 21: 43–50.
van Acker BA, Koomen GC, Koopman MG, et al. Discrepancy between circadian rhythms of inulin and creatinine clearance. J Lab Clin Med. 1992; 120: 400–10.
Koopman MG, Koomen GC, Krediet RT, et al. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci. 1989; 77: 105–11.
Williams LR, Leggett RW. Reference values for resting blood flow to organs of man. Clin Phys Physiol Meas. 1989; 10: 187–217.
West JB, editor. Best and Taylor’s physiological basis of medical practice. 11th ed. Baltimore: Williams & Wilkins, 1985.
Waddell WJ, Butler TC. The distribution and excretion of phenobarbital. J Clin Invest. 1957; 36: 1217–26.
Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992; 85: 803–7.
Besseghir K, Roch-Ramel F. Renal excretion of drugs and other xenobiotics. Renal Physiol. 1987; 10: 221–41.
Moller JV, Skeikh MI. Renal organic anion transport system: pharmacological, physiological, and biochemical aspects. Pharmacol Rev. 1983; 34: 315–58.
Pritchard JB, Miller DS. Comparative insights into the mechanisms of renal organic anion and cation secretion. Am J Physiol. 1991; 261: R1329–40.
Brown GR. Cephalosporin-probenecid drug interactions. Clin Pharmacokinet. 1993; 24: 289–300.
Handsfield HH. Recent developments in gonorrhea and pelvic inflammatory disease. J Med. 1983; 14: 281–305.
Speeg KV, Leighton JV, Maldonado AL. Toxic delerium in a patient taking amantadine and trimethoprim/sulfamethoxazole. Am J Med Sci. 1989; 298: 410–2.
Robinson PJ, Rapoport SI. The kinetics of protein binding determine the rate of uptake of drugs by the brain. Am J Physiol. 1986; 251: R1212–20.
Inoue M, Okajima K, Ando Y, et al. Mechanism of furosemide resistance by analbumininemic rats and hypoalbuminemic patients. Kidney Int. 1987; 32: 198–203.
Smith HW. Lectures on the kidney. Lawrence: University of Kansas, 1943.
Ullrich KJ, Rumrich G. Contraluminal transport systems in the proximal renal tubules involved in secretion of organic ions. Am J Physiol. 1988; 254: F453–62.
Burkhardt G, Ullrich KJ. Organic anion transport across the contraluminal membrane KJ dependence on sodium. Kidney Int. 1989; 36: 370–7.
Spencer AM, Sack J, Hong SK. Relationship between PAH transport and Na-K-ATPase activity in the rabbit kidney. Am J Physiol. 1979; 236: F126–30.
Dantzler WH. K+ effects on PAH transport and permeabilities in isolate snake renal tubules. Am J Physiol. 1974; 227: 1361–70.
Dantzler WH, Brokl OH. Effects of low [Ca2+] and La[3+] on PAH transport by isolated perfused renal tubules. Am J Physiol. 1984; 246: F175–87.
Somogyi A, Gugler R. Drug interactions with cimetidine. Clin Pharmacokinet. 1982; 7: 23–41.
Rennick BR. Renule tubule transport of organic cations. Am J Physiol. 1981; 240: F83–9.
Kinsella JL, Holohan PD, Pessah NI, et al. Transport of organic ions in renal cortical luminal and anitluminal membrane vesicles. J Pharmacol Exp Ther. 1979; 209: 443–50.
van Crugten J, Bochner F, Keal J, et al. Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans. Studies with anionic, cationic and zwitterionic drugs. J Pharmacol Exp Ther. 1986; 236: 481–7.
Gower PE, Dash CH. Cephalexin, human studies of absorption and excretion of a new cephalosproin antibiotic. Br J Pharmacol. 1969; 37: 738–47.
Carr RA, Pasutto FM, Foster RT. Infleunce of cimetidine coadministration on the pharmacokinetics of sotalol enantiomers in an anesthetized rat model: evidence supporting active renal excretion of sotalol. Biopharm Drug Dispos. 1996; 17: 55–69.
Litterst CL, Mimnaugh EG, Reagan RL, et al. Comparison of in vitro drug metabolism by the lung, liver, and kidney of several common laboratory species. Drug Metab Dispos. 1975; 3: 259–65.
Vree TB, Hekster YA, Anderson PG. Contribution of the human kidney to the metabolic clearance of drugs. Ann Pharmacother. 1992; 26: 1421–8.
Vree TB, Beneken Kolmer EWJ, Martea M, et al. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfa-6-monomethoxine in humans. Pharm Weekbl Sci. 1990; 12: 71–5.
Vree TB, Beneken Kolmer EWJ, Hekster YA. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfamethomidine in humans. Pharm Weekbl Sci. 1991; 13: 198–206.
Vree TB, Beneken Kolmer EWJ, Hekster YA, et al. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfa-6-monomethoxine in humans. Drug Metab Dispos. 1990; 18: 852–8.
Mazoit JX, Sandouk P, Schermann JM, et al. Extrahepatic metabolism of morphine occurs in humans. Clin Pharmacol Ther. 1990; 48: 613–8.
Howe JL, Back DJ, Colbert J. Extrahepatic metabolism of zidovudine. Br J Clin Pharmacol. 1992; 33: 190–2.
Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet. 1994; 26: 144–60.
Bendayan R. Renal drug transport: a review. Pharmacotherapy. 1996; 16: 971–85.
Gatmaitan ZC, Arias IM. Structure and function of p-glycoprotein in normal liver and small intestine. Adv Pharmacol. 1993; 24: 77–97.
Dudley A, Brown C. Mediation of cimetidine secretionby p-glycoprotein and a novel H+− couple mechanism in cultured renal epithilial monolayers of LLC-PK1 cells. Br J Pharmacol. 1996; 117: 1139–44.
Charuk J, Wong P, Reithmeier R. Differential interaction of human renal p-glycoprotein with various metabolites and analogues of cyclosporin A. Am J Physiol. 1995; 269: F31–9.
Tucker GT. Measurement of the renal clearance of drugs. Br J Clin Pharmacol. 1981; 12: 761–70.
Martin BK. Drug urinary excretion data: some aspects concerning interpretation. Br J Pharmacol. 1967; 29: 181–93.
Roy T. Fitting a straight line when both variables are subject to error: pharmaceutical applications. J Pharm Biomed Anal. 1994; 12: 1265–9.
Reilman MA, Gunst RF, Lakshminarayanan MY. Stochastic regression with errors in both variables. J Qual Technol. 1986; 18: 162–9.
Levy G. Effect of plasma protein binding on renal clearance of drugs. J Pharm Sci. 1980; 69: 482–3.
Bricker NS, Klahr S, Lubowitz H, et al. Renal function in chronic renal disease. Medicine. 1965; 44: 263–88.
Dixon M, Webb EC. Enzymes. 3rd ed. New York: Academic Press, 1979.
Gyory AZ, Lingard JM. Kinetics of active sodium transport in rat proximal tubules and its variation by cardiac glycosides at zero net volume and ion fluxes: evidence for a multisite sodium transport system. J Physiol. 1976; 257: 251–1A.
Hekman P, van Kineken CA. Simultaneous kinetic modelling of plasma levels and urinary excretion of salicyluric acid, and the influence of probenecid. Eur J Drug Metab Pharmacokinet. 1983; 8: 239–49.
Upton RA, Williams RL, Bushkin JN, et al. Effects of probenecid on ketoprofen pharmacokinetics. Clin Pharmacol Ther. 1982; 31: 705–12.
van Ginneken CAM, Russel FGM. Saturable pharmacokinetics in the renal excretion of drugs. Clin Pharmacokinet. 1989; 16: 38–54.
Bekersky I. The isolated perfused kidney as a pharmacological tool. Trends Pharmacol Sci. 1983; 4: 6–7.
Vickers AEM, Fischer V, Connors S, et al. Cyclosporin A metabolism in human liver, kidney, and intestine slices. Drug Metab Dispos. 1992; 20: 802–9.
Connors MS, Larrauri A, Dannecker R, et al. Biotransformation of a somatostatin analogue in precision-cut liver and kidney slices from rat, dog, and man. Xenobiotica. 1996; 26: 133–41.
Siebe H, Baude G, Lichtenstein I, et al. Metabolism of dexamethasone: sites and activity in mammalian tissues. Renal Physiol Biochem. 1993; 16: 79–88.
Lensmeyer GL, Wiebe AA, Carlson TH, et al. Concentrations of cyclosporin A and its metabolites in human tissue postmortem. J Anal Toxicol. 1991; 15: 110–5.
Nelson JA, Santos G, Herbert BH. Mechanisms for the renal secretion of cisplatin. Cancer Treat Rep. 1984; 68: 849–53.
Spector R. Riboflavin transport by rabbit kidney slices: characterization and relation to cyclic organic acid transport. J Pharmacol Exp Ther. 1982; 221: 394–8.
Ott RJ, Hui AC, Yuan G, et al. Organic cation transport in human renal brush-border membrane vesicles. Am J Physiol. 1991; 261: F443–51.
Hassal CD, Gandolfi AJ, Brendel K. Correlation of the in vivo and in vitro renal toxicity of S-(1,2-dichlorovinyl)-L-cyste-ine. Drug Chem Toxicol. 1983; 6: 507–20.
Jaffe DR, Hassall CD, Brendel K, et al. In vivo and in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene. J Toxicol Environ Health. 1983; 11: 857–67.
Okudaira N, Sugiyama Y. Use of an isolated perfused kidney to assess renal clearance of drugs. In: Borchardt RT, editor. Models for assessing drug absorption and metabolism. New York: Plenum Press, 1996: 211–38.
Brett CM, Washington CB, Ott RJ, et al. Interaction of nucleoside analogues with the sodium-nucleoside transport system in brush border membrane vesicles from human kidney. Pharm Res. 1993; 10: 423–6.
Gutierrez MM, Giacomini KM. Substrate selectivity, potential sensitivity and stoichiometry of Na+ -nucleoside transport in brush border membrane vesicles from human kidney. Biochim Biophys Acta. 1993; 1149: 202–8.
Gutierrez MM, Brett CM, Ott RJ, et al. Nucleoside transport in brush border membrane vesicles from human kidney. Biochim Biophys Acta. 1992; 1105: 1–9.
Vijayalakshmi D, Belt JA. Sodium-dependent nucleoside transport in mouse intestinal epithelial cells: two transport systems with differing substrate specificities. J Biol Chem. 1988; 263: 19419–23.
Lee CW, Chesseman CI, Jarvis SM. Transport characteristics of renal brush border Na+− and K+-dependent uridine carriers. Am J Physiol. 1990; 258: F1203–10.
Bekersky I. Use of the isolated perfused kidney as a tool in drug disposition studies. Drug Metab Rev. 1983; 14: 931–60.
Maack T. Renal clearance and isolated perfusion techniques. Kidney Int. 1986; 30: 142–51.
Boom SPA, Moons MM, Russel FGM. Renal tubular transport of cimetidine in the isolated perfused kidney in the rat. Drug Metab Dispos. 1994; 22: 148–53.
Wan S, Riegelman S. Renal contribution to overall metabolism of drugs. II: biotransformation of salicylic acid to salicyluric acid. J Pharm Sci. 1972; 61: 1284–7.
Ahn H, Jamali F, Cox SR, et al. Stereoselective disposition of ibuprofen enantiomers in the isolated perfused rat kidney. Pharm Res. 1991; 8: 1520–4.
de Lennoy IAM, Hirayama H, Pang KS. A physiological model for renal drug metabolism: enalapril esterolysis to enalaprilat in the isolated perfused kidney. J Pharmacokinet Biopharm. 1990; 18: 561–87.
McElnay JC, D’Arcy PF. Sites and mechanisms of drug interactions. II: protein binding, renal excretion and pharmacodynamic interactions. Int J Pharm. 1980; 6: 205–23.
Martin SW, Broadley KJ. Renal vasodilatation by dopexamine and fenoldapam due to a1-adrenoceptor blockade. Br J Pharmacol. 1995; 115: 349–55.
Li T, Croce K, Winquist RJ. Vasocontrictor and vasodilator effects of serotonin in the isolated rabbit kidney. J Pharmacol Exp Ther. 1992; 263: 928–32.
Castellucci A, Maggi CA, Evangelista S. Calcitonin gene-related peptide (CGRP)1 receptor mediates vasodilation in the rat isolated and perfused kidney. Life Sci. 1993; 53: 153–8.
Smith DE, Guillard S, Rodriguez CA. Effect of angiotensin II-induced changes in perfusion flow rate on chlorothiazide transport in the isolated perfused kidney. J Pharmacokinet Biopharm. 1992; 20: 195–207.
Lee L, Cook JA, Smith DE. Renal transport kinetics of chlorothiazide in the isolated perfused kidney. J Pharmacol Exp Ther. 1988; 247: 203–8.
Lee L, Cook JA, Smith DE. Renal transport kinetics of furosemide in the isolated perfused kidney. J Pharmacokinet Biopharm. 1986; 14: 157–74.
Rodriguez CA, Smith DE. Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys. Antimicrob Agents Chemother. 1991; 35: 2395–400.
Sweeney KR, Hsyu P, Statkevich P, et al. Renal disposition and drug interaction screening of (−)-2′-deoxy-3′-thiacytidine (3TC) in the isolated perfused rat kidney. Pharm Res. 1995; 12: 1958–63.
Linn JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos. 1996; 23: 1008–21.
Hinderling PH, Dilea C, Koziol T, et al. Comparative kinetics of sematilide in four species. Drug Metab Dispos. 1993; 21: 662–9.
Swabb E, Bonner D. Prediction of aztreonam pharmacokinetics in humans based on data from animals. J Pharmacokinet Biopharm. 1983; 11: 215–23.
Boxenbaum H, D’souza RW. Interspecies pharmacokinetic scaling, biolgical design, and neoteny. In: Testa B, editor. Advances in drug research. London: Academic Press, 1991: 1–116.
Sawada Y, Hanano M, Sugiyama Y, et al. Prediction of the volumes of distribution of basic drugs in humans based on data from animals. J Pharmacokinet Biopharm. 1984; 12: 587–96.
Neilson P, Rasmussen F. Halflife and renal excretion of trimethoprim in swine. Acta Pharmacol Toxicol. 1975; 36: 123–31.
Burtin M, Elghozi J, Laude D, et al. Speciies differences in mammalian renal function: 5-HIAA, a reported marker of tubular secretion in humans, is handled exclusively by filtration in the rat. Exp Nephrol. 1993; 1: 62–4.
Rasmussen F. Renal clearance: species differences and similarities. Vet Res Commun. 1983; 7: 301–6.
Biggi A, Viglietti A, Farinelli MC, et al. Estimation of glomerular filtration using chromium-51 diamine tetra-acetic acid and technetium-99m diethylene triamine penta-acetic acid. Eur J Nucl Med. 1995; 22: 532–6.
Fleming JS, Wilkinson J, Oliver RM, et al. Comparison of radionuclide estimation of glomerular filtration using technetium-99m diethylenetriaminepentaacetic acid and chromium-51 ethylenediaminetetraacetic acid. Eur J Nucl Med. 1991; 18: 391–5.
Effersoe H, Rosenkilde P, Groth S, et al. Measurement of renal function with iohexol: a comparison of iohexol, 99m-Tc-DPTA, and 51Cr-EDTA clearance. Invest Radiol. 1990; 25: 778–82.
Frennby B. Use of iohexol clearance to determine glomerular filtration rate: a comparison between different clearance techniques in man and animal. Scand J Urol Nephrol 1997; 182 Suppl.: 1–63.
Schuster VL, Seldin DW. Renal clearance. In: Seidin DW, Giebisch G, editors. The kidney: physiology and pathophysiology. Vol. I. New York: Raven Press, 1985: 365–95.
Smith HW. The kidney: structure and function in health and disease. New York: Oxford University Press, 1951.
Mujais SK, Quintanilla A, Zahid M, et al. Renal handling of enalaprilat. Am J Kidney Dis. 1992; 19: 121–5.
Reubi FC. Clearance tests in clinical medicine. Springfield: C.C. Thomas, 1963.
Brod J, Sterzel RB. Conventional measurements for renal clearance measurements in man. Contrib Nephrol. 1978; 11: 1–9.
Levey AS, Perrone RD, Madias NE. Serum creatinine and renal function. Ann Rev Med. 1988; 39: 465–90.
Lemmer B. Tagesrhyhtm and Arzneitittelwirkung. In: Lemmer B, editor. Chronopharmakokinetik. 2nd ed. Stutgart: Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1984.
Hull JH, Hak LJ, Kock GG. Influence of range of renal function and liver disease on predictability of renal clearance. Clin Pharmacol Ther. 1981; 29: 516–21.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31–41.
Mawer EG, Knowles BR, Lucas SB, et al. Computer assisted prescribing of kanamycin for patients with renal insufficiency. Lancet. 1972; I: 12–5.
Jelliffe RW. Creatinine clearance: a bedside estimate. Ann Intern Med. 1973; 79: 604–5.
Robertshaw M, Lai KN, Swaminathan R. Prediction of creatinine clearance from plasma: comparison of five formula. Br J Clin Pharmacol. 1989; 28: 275–80.
Luke DR, Halstenson CE, Opsahl JA, et al. Validity of creatinine clearance estimates in the assessment of renal function. Clin Pharmacol Ther. 1990; 48: 503–8.
Uhl S, Schmid P, Schlatter C. Pharmacokinetics of pentachlorophenol in man. Arch Toxicol. 1986; 58: 182–6.
Skoutakis VA. Clinical toxicology of drugs: principles and practice. Philadelphia: Lea & Febiger, 1982.
Chiou WL. A new simple approach to study the effect of changes in urine flow and/or urine pH on renal clearance and its applications. Int J Clin Pharmacol Ther Toxicol. 1986; 24: 519–27.
Berndt A, Gramatte T, Oertel R, et al. Day-night variations in the renal excretion of the antiarrhythmic tiracizine and its metabolites. Chronobiol Int. 1995; 12: 135–40.
Gilman AG, Goodman LS, Rall TS, et al, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 7th ed. New York: MacMillan Publishing Company, 1985.
Huff JW, Perzweig WA. N-1-methylnicotinamide, a metabolite of nicotinic acid in the urine. J Biol Chem. 1943; 150: 395–400.
Nasseri K, Daley-Yates FT. Acomparison of N-1-methylnicotinamide clearance with five other markers of renal function in models of acute and chronic renal failure. Toxicol Lett. 1990; 53: 231–45.
Maiza A, Daley-Yates PT. Variability in the renal clearance of cephalexin in experimental renal failure. J Pharmacokinet Biopharm. 1993; 21: 19–30.
Somogyi A, McLean A, Heinzow B. Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol. 1983; 25: 339–45.
Dossing M, Pilsgaard H, Rasmussen B, et al. Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism. Eur J Clin Pharmacol.. 1983; 25: 215–22.
Feely J, Wilkinson GR, Wood AU. Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med. 1981; 304: 692–5.
Feely J, Wilkinson GR, McAllister CB, et al. Increased toxicity and reduced clearance of lidocaine by cimetidine. Ann Intern Med. 1982; 96: 592–4.
Cunningham RF, Israili ZH, Dayton PG. Clinical pharmacokinetics of probenecid. Clin Pharmacokinet. 1981; 6: 135–51.
Jaehde U, Sorgel F, Reiter A, et al. Effect of probenecid on the distribution and elimination of ciprofloxacin in humans. Clin Pharmacol Ther. 1995; 58: 532–41.
Bauer L, Horn JR, Pettit H. Mixed-effect modeling for detection and evaluation of drug-drug interactions: digoxin-quinidine and digoxin-verapamil combinations. Ther Drug Monit. 1996; 18: 46–52.
Grasela TH, Antal EJ, Ereshefsky L, et al. An evaluation of population pharmacokinetics in therapeutic trials. II: detection of a drug-drug interaction. Clin Pharmacol Ther. 1987; 42: 433–41.
Sjostrom PA, Odlind BG, Wolgast M. Extensive tubular secretion and reabsorption of creatinine in humans. Scand J Urol Nephrol. 1988; 22: 129–31.
El-Tahtawy AA, Jackson AJ, Ludden TM. Comparison of single and multiple dose pharmacokinetics using clinical bioequivalence data and monte carlo simulations. Pharm Res. 1994; 11: 1330–6.
Chow S-C, Liu J-P. Design and analysis of bioavailability and bioequivalence studies. New York: Marcell Dekker, 1992.
Ratkowsky DA, Evans MA, Alldredge JR. Cross-over experiments: design, analysis and application. New York: Marcell Dekker, 1993.
About this article
Cite this article
Bonate, P.L., Reith, K. & Weir, S. Drug Interactions at the Renal Level. Clin Pharmacokinet 34, 375–404 (1998). https://doi.org/10.2165/00003088-199834050-00004