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Drug Interactions at the Renal Level

Implications for Drug Development

Clinical Pharmacokinetics volume 34, pages 375–404 (1998)Cite this article

Abstract

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.

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References

  1. Vander AJ, Sherman JH, Luciano DS. Human physiology. New York: McGraw-Hill, 1990.

    Google Scholar 

  2. Narayanan S. Renal biochemistry and physiology: pathophysiology and analytical perspectives. Adv Clin Chem. 1992; 29: 121–59.

    Article  PubMed  CAS  Google Scholar 

  3. 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.

    Article  PubMed  CAS  Google Scholar 

  4. 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.

    PubMed  Google Scholar 

  5. Koopman MG, Koomen GC, Krediet RT, et al. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci. 1989; 77: 105–11.

    PubMed  CAS  Google Scholar 

  6. Williams LR, Leggett RW. Reference values for resting blood flow to organs of man. Clin Phys Physiol Meas. 1989; 10: 187–217.

    Article  PubMed  CAS  Google Scholar 

  7. West JB, editor. Best and Taylor’s physiological basis of medical practice. 11th ed. Baltimore: Williams & Wilkins, 1985.

    Google Scholar 

  8. Waddell WJ, Butler TC. The distribution and excretion of phenobarbital. J Clin Invest. 1957; 36: 1217–26.

    Article  PubMed  CAS  Google Scholar 

  9. Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992; 85: 803–7.

    Article  PubMed  CAS  Google Scholar 

  10. Besseghir K, Roch-Ramel F. Renal excretion of drugs and other xenobiotics. Renal Physiol. 1987; 10: 221–41.

    PubMed  CAS  Google Scholar 

  11. Moller JV, Skeikh MI. Renal organic anion transport system: pharmacological, physiological, and biochemical aspects. Pharmacol Rev. 1983; 34: 315–58.

    Google Scholar 

  12. Pritchard JB, Miller DS. Comparative insights into the mechanisms of renal organic anion and cation secretion. Am J Physiol. 1991; 261: R1329–40.

    PubMed  CAS  Google Scholar 

  13. Brown GR. Cephalosporin-probenecid drug interactions. Clin Pharmacokinet. 1993; 24: 289–300.

    Article  PubMed  CAS  Google Scholar 

  14. Handsfield HH. Recent developments in gonorrhea and pelvic inflammatory disease. J Med. 1983; 14: 281–305.

    PubMed  CAS  Google Scholar 

  15. Speeg KV, Leighton JV, Maldonado AL. Toxic delerium in a patient taking amantadine and trimethoprim/sulfamethoxazole. Am J Med Sci. 1989; 298: 410–2.

    Article  PubMed  CAS  Google Scholar 

  16. 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.

    PubMed  CAS  Google Scholar 

  17. Inoue M, Okajima K, Ando Y, et al. Mechanism of furosemide resistance by analbumininemic rats and hypoalbuminemic patients. Kidney Int. 1987; 32: 198–203.

    Article  PubMed  CAS  Google Scholar 

  18. Smith HW. Lectures on the kidney. Lawrence: University of Kansas, 1943.

    Google Scholar 

  19. 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.

    PubMed  CAS  Google Scholar 

  20. Burkhardt G, Ullrich KJ. Organic anion transport across the contraluminal membrane KJ dependence on sodium. Kidney Int. 1989; 36: 370–7.

    Article  Google Scholar 

  21. 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.

    PubMed  CAS  Google Scholar 

  22. Dantzler WH. K+ effects on PAH transport and permeabilities in isolate snake renal tubules. Am J Physiol. 1974; 227: 1361–70.

    PubMed  CAS  Google Scholar 

  23. 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.

    PubMed  CAS  Google Scholar 

  24. Somogyi A, Gugler R. Drug interactions with cimetidine. Clin Pharmacokinet. 1982; 7: 23–41.

    Article  PubMed  CAS  Google Scholar 

  25. Rennick BR. Renule tubule transport of organic cations. Am J Physiol. 1981; 240: F83–9.

    PubMed  CAS  Google Scholar 

  26. 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.

    PubMed  CAS  Google Scholar 

  27. 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.

    PubMed  Google Scholar 

  28. Gower PE, Dash CH. Cephalexin, human studies of absorption and excretion of a new cephalosproin antibiotic. Br J Pharmacol. 1969; 37: 738–47.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    PubMed  CAS  Google Scholar 

  31. Vree TB, Hekster YA, Anderson PG. Contribution of the human kidney to the metabolic clearance of drugs. Ann Pharmacother. 1992; 26: 1421–8.

    PubMed  CAS  Google Scholar 

  32. 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.

    Article  PubMed  Google Scholar 

  33. Vree TB, Beneken Kolmer EWJ, Hekster YA. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfamethomidine in humans. Pharm Weekbl Sci. 1991; 13: 198–206.

    Article  PubMed  CAS  Google Scholar 

  34. 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.

    PubMed  CAS  Google Scholar 

  35. Mazoit JX, Sandouk P, Schermann JM, et al. Extrahepatic metabolism of morphine occurs in humans. Clin Pharmacol Ther. 1990; 48: 613–8.

    Article  PubMed  CAS  Google Scholar 

  36. Howe JL, Back DJ, Colbert J. Extrahepatic metabolism of zidovudine. Br J Clin Pharmacol. 1992; 33: 190–2.

    Article  PubMed  CAS  Google Scholar 

  37. Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet. 1994; 26: 144–60.

    Article  PubMed  CAS  Google Scholar 

  38. Bendayan R. Renal drug transport: a review. Pharmacotherapy. 1996; 16: 971–85.

    PubMed  CAS  Google Scholar 

  39. Gatmaitan ZC, Arias IM. Structure and function of p-glycoprotein in normal liver and small intestine. Adv Pharmacol. 1993; 24: 77–97.

    Article  PubMed  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    PubMed  CAS  Google Scholar 

  42. Tucker GT. Measurement of the renal clearance of drugs. Br J Clin Pharmacol. 1981; 12: 761–70.

    Article  PubMed  CAS  Google Scholar 

  43. Martin BK. Drug urinary excretion data: some aspects concerning interpretation. Br J Pharmacol. 1967; 29: 181–93.

    CAS  Google Scholar 

  44. Roy T. Fitting a straight line when both variables are subject to error: pharmaceutical applications. J Pharm Biomed Anal. 1994; 12: 1265–9.

    Article  PubMed  CAS  Google Scholar 

  45. Reilman MA, Gunst RF, Lakshminarayanan MY. Stochastic regression with errors in both variables. J Qual Technol. 1986; 18: 162–9.

    Google Scholar 

  46. Levy G. Effect of plasma protein binding on renal clearance of drugs. J Pharm Sci. 1980; 69: 482–3.

    Article  PubMed  CAS  Google Scholar 

  47. Bricker NS, Klahr S, Lubowitz H, et al. Renal function in chronic renal disease. Medicine. 1965; 44: 263–88.

    Article  PubMed  CAS  Google Scholar 

  48. Dixon M, Webb EC. Enzymes. 3rd ed. New York: Academic Press, 1979.

    Google Scholar 

  49. 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.

    Google Scholar 

  50. 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.

    Article  PubMed  CAS  Google Scholar 

  51. Upton RA, Williams RL, Bushkin JN, et al. Effects of probenecid on ketoprofen pharmacokinetics. Clin Pharmacol Ther. 1982; 31: 705–12.

    Article  PubMed  CAS  Google Scholar 

  52. van Ginneken CAM, Russel FGM. Saturable pharmacokinetics in the renal excretion of drugs. Clin Pharmacokinet. 1989; 16: 38–54.

    Article  PubMed  Google Scholar 

  53. Bekersky I. The isolated perfused kidney as a pharmacological tool. Trends Pharmacol Sci. 1983; 4: 6–7.

    Article  Google Scholar 

  54. 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.

    PubMed  CAS  Google Scholar 

  55. 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.

    Article  PubMed  CAS  Google Scholar 

  56. Siebe H, Baude G, Lichtenstein I, et al. Metabolism of dexamethasone: sites and activity in mammalian tissues. Renal Physiol Biochem. 1993; 16: 79–88.

    PubMed  CAS  Google Scholar 

  57. 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.

    PubMed  CAS  Google Scholar 

  58. Nelson JA, Santos G, Herbert BH. Mechanisms for the renal secretion of cisplatin. Cancer Treat Rep. 1984; 68: 849–53.

    PubMed  CAS  Google Scholar 

  59. Spector R. Riboflavin transport by rabbit kidney slices: characterization and relation to cyclic organic acid transport. J Pharmacol Exp Ther. 1982; 221: 394–8.

    PubMed  CAS  Google Scholar 

  60. 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.

    PubMed  CAS  Google Scholar 

  61. 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.

    Article  Google Scholar 

  62. 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.

    Article  PubMed  CAS  Google Scholar 

  63. 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.

    Google Scholar 

  64. 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.

    Article  PubMed  CAS  Google Scholar 

  65. 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.

    Article  PubMed  CAS  Google Scholar 

  66. 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.

    Article  PubMed  CAS  Google Scholar 

  67. 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.

    PubMed  CAS  Google Scholar 

  68. 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.

    PubMed  CAS  Google Scholar 

  69. Bekersky I. Use of the isolated perfused kidney as a tool in drug disposition studies. Drug Metab Rev. 1983; 14: 931–60.

    Article  PubMed  CAS  Google Scholar 

  70. Maack T. Renal clearance and isolated perfusion techniques. Kidney Int. 1986; 30: 142–51.

    Article  PubMed  CAS  Google Scholar 

  71. 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.

    PubMed  CAS  Google Scholar 

  72. 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.

    Article  PubMed  CAS  Google Scholar 

  73. 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.

    Article  PubMed  CAS  Google Scholar 

  74. 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.

    Google Scholar 

  75. 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.

    Article  CAS  Google Scholar 

  76. Martin SW, Broadley KJ. Renal vasodilatation by dopexamine and fenoldapam due to a1-adrenoceptor blockade. Br J Pharmacol. 1995; 115: 349–55.

    Article  PubMed  CAS  Google Scholar 

  77. 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.

    PubMed  CAS  Google Scholar 

  78. 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.

    Article  Google Scholar 

  79. 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.

    PubMed  CAS  Google Scholar 

  80. Lee L, Cook JA, Smith DE. Renal transport kinetics of chlorothiazide in the isolated perfused kidney. J Pharmacol Exp Ther. 1988; 247: 203–8.

    PubMed  CAS  Google Scholar 

  81. Lee L, Cook JA, Smith DE. Renal transport kinetics of furosemide in the isolated perfused kidney. J Pharmacokinet Biopharm. 1986; 14: 157–74.

    PubMed  CAS  Google Scholar 

  82. 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.

    Article  PubMed  CAS  Google Scholar 

  83. 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.

    Article  PubMed  CAS  Google Scholar 

  84. Linn JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos. 1996; 23: 1008–21.

    Google Scholar 

  85. Hinderling PH, Dilea C, Koziol T, et al. Comparative kinetics of sematilide in four species. Drug Metab Dispos. 1993; 21: 662–9.

    PubMed  CAS  Google Scholar 

  86. Swabb E, Bonner D. Prediction of aztreonam pharmacokinetics in humans based on data from animals. J Pharmacokinet Biopharm. 1983; 11: 215–23.

    PubMed  CAS  Google Scholar 

  87. 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.

    Google Scholar 

  88. 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.

    PubMed  CAS  Google Scholar 

  89. Neilson P, Rasmussen F. Halflife and renal excretion of trimethoprim in swine. Acta Pharmacol Toxicol. 1975; 36: 123–31.

    Google Scholar 

  90. 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.

    PubMed  CAS  Google Scholar 

  91. Rasmussen F. Renal clearance: species differences and similarities. Vet Res Commun. 1983; 7: 301–6.

    Article  PubMed  CAS  Google Scholar 

  92. 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.

    Article  PubMed  CAS  Google Scholar 

  93. 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.

    Article  PubMed  CAS  Google Scholar 

  94. 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.

    Article  PubMed  CAS  Google Scholar 

  95. 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.

    CAS  Google Scholar 

  96. 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.

    Google Scholar 

  97. Smith HW. The kidney: structure and function in health and disease. New York: Oxford University Press, 1951.

    Google Scholar 

  98. Mujais SK, Quintanilla A, Zahid M, et al. Renal handling of enalaprilat. Am J Kidney Dis. 1992; 19: 121–5.

    PubMed  CAS  Google Scholar 

  99. Reubi FC. Clearance tests in clinical medicine. Springfield: C.C. Thomas, 1963.

    Google Scholar 

  100. Brod J, Sterzel RB. Conventional measurements for renal clearance measurements in man. Contrib Nephrol. 1978; 11: 1–9.

    PubMed  CAS  Google Scholar 

  101. Levey AS, Perrone RD, Madias NE. Serum creatinine and renal function. Ann Rev Med. 1988; 39: 465–90.

    Article  PubMed  CAS  Google Scholar 

  102. Lemmer B. Tagesrhyhtm and Arzneitittelwirkung. In: Lemmer B, editor. Chronopharmakokinetik. 2nd ed. Stutgart: Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1984.

    Google Scholar 

  103. 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.

    Article  PubMed  CAS  Google Scholar 

  104. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31–41.

    Article  PubMed  CAS  Google Scholar 

  105. Mawer EG, Knowles BR, Lucas SB, et al. Computer assisted prescribing of kanamycin for patients with renal insufficiency. Lancet. 1972; I: 12–5.

    Article  Google Scholar 

  106. Jelliffe RW. Creatinine clearance: a bedside estimate. Ann Intern Med. 1973; 79: 604–5.

    PubMed  CAS  Google Scholar 

  107. Robertshaw M, Lai KN, Swaminathan R. Prediction of creatinine clearance from plasma: comparison of five formula. Br J Clin Pharmacol. 1989; 28: 275–80.

    Article  PubMed  CAS  Google Scholar 

  108. 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.

    Article  PubMed  CAS  Google Scholar 

  109. Uhl S, Schmid P, Schlatter C. Pharmacokinetics of pentachlorophenol in man. Arch Toxicol. 1986; 58: 182–6.

    Article  PubMed  CAS  Google Scholar 

  110. Skoutakis VA. Clinical toxicology of drugs: principles and practice. Philadelphia: Lea & Febiger, 1982.

    Google Scholar 

  111. 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.

    PubMed  CAS  Google Scholar 

  112. 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.

    Article  PubMed  CAS  Google Scholar 

  113. 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.

    Google Scholar 

  114. Huff JW, Perzweig WA. N-1-methylnicotinamide, a metabolite of nicotinic acid in the urine. J Biol Chem. 1943; 150: 395–400.

    CAS  Google Scholar 

  115. 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.

    Article  Google Scholar 

  116. Maiza A, Daley-Yates PT. Variability in the renal clearance of cephalexin in experimental renal failure. J Pharmacokinet Biopharm. 1993; 21: 19–30.

    PubMed  CAS  Google Scholar 

  117. 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.

    Article  PubMed  CAS  Google Scholar 

  118. 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.

    Article  PubMed  CAS  Google Scholar 

  119. Feely J, Wilkinson GR, Wood AU. Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med. 1981; 304: 692–5.

    Article  PubMed  CAS  Google Scholar 

  120. Feely J, Wilkinson GR, McAllister CB, et al. Increased toxicity and reduced clearance of lidocaine by cimetidine. Ann Intern Med. 1982; 96: 592–4.

    PubMed  CAS  Google Scholar 

  121. Cunningham RF, Israili ZH, Dayton PG. Clinical pharmacokinetics of probenecid. Clin Pharmacokinet. 1981; 6: 135–51.

    Article  PubMed  CAS  Google Scholar 

  122. 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.

    Article  PubMed  CAS  Google Scholar 

  123. 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.

    Article  PubMed  CAS  Google Scholar 

  124. 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.

    Article  PubMed  Google Scholar 

  125. Sjostrom PA, Odlind BG, Wolgast M. Extensive tubular secretion and reabsorption of creatinine in humans. Scand J Urol Nephrol. 1988; 22: 129–31.

    Article  PubMed  CAS  Google Scholar 

  126. 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.

    Article  PubMed  CAS  Google Scholar 

  127. Chow S-C, Liu J-P. Design and analysis of bioavailability and bioequivalence studies. New York: Marcell Dekker, 1992.

    Google Scholar 

  128. Ratkowsky DA, Evans MA, Alldredge JR. Cross-over experiments: design, analysis and application. New York: Marcell Dekker, 1993.

    Google Scholar 

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  1. Hoechst Marion Roussel, US Pharmacokinetics, P.O. Box 9627 (F4-M3112), Kansas City, Missouri, 64134, USA

    Peter L. Bonate, Kelly Reith & Scott Weir

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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

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  • DOI: https://doi.org/10.2165/00003088-199834050-00004

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