European Journal of Clinical Pharmacology

, Volume 65, Issue 8, pp 757–773 | Cite as

Pharmacokinetics and dosage adjustment in patients with renal dysfunction

  • Roger K. VerbeeckEmail author
  • Flora T. Musuamba
Review Article



Chronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment.


Inappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft–Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required.


According to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drug's pharmacokinetics and pharmacodynamics.


In conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common.


Dosage adjustment Non-renal drug clearance Pharmacokinetic/pharmacodynamic processes Renal dysfunction Renal drug clearance 


  1. 1.
    Thummel KE, Shen DD, Isoherranen N, Smith HE (2006) Design and optimization of dosage regimens: pharmacokinetic data. In: Brunton LL, Lazo LL, Parker KL (eds) Goodman & Gilman’s The pharmacological basis of therapeutics, 11 edn. McGraw-Hill, New York, pp 1787–1888Google Scholar
  2. 2.
    Coresh J, Selvin E, Stevens LA et al (2007) Prevalence of chronic kidney disease in the United States. JAMA 298:2038–2047PubMedCrossRefGoogle Scholar
  3. 3.
    Graves JW (2008) Diagnosis and management of chronic kidney disease. Mayo Clin Proc 83:1064–1069PubMedCrossRefGoogle Scholar
  4. 4.
    Stevens LA, Coresh J, Greene T, Levey AS (2006) Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med 354:2473–2483PubMedCrossRefGoogle Scholar
  5. 5.
    Tett SE, Kirkpatrick CMJ, Gross AS, McLachlan AJ (2003) Principles and clinical application of assessing alterations in renal elimination pathways. Clin Pharmacokinet 42:1193–1211PubMedCrossRefGoogle Scholar
  6. 6.
    de Jong PE, Gansevoort RT (2008) Fact or fiction of the epidemic of chronic kidney disease—let us not squabble about estimated GFR only, but also focus on albuminuria. Nephrol Dial Transplant 23:1092–1095PubMedCrossRefGoogle Scholar
  7. 7.
    Gaspari F, Perico N, Remuzzi G (1998) Application of newer clearance techniques for the determination of glomerular filtration rate. Curr Opin Nephrol Hypertens 7:675–680PubMedGoogle Scholar
  8. 8.
    Cockroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefGoogle Scholar
  9. 9.
    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 130:461–470PubMedGoogle Scholar
  10. 10.
    Levey AS, Greene T, Kusk JW, Beck GJ, MDRD Study Group (2000) A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 11:A0828 (Abstract)Google Scholar
  11. 11.
    Bostom AG, Kronenberg F, Eberhard R (2002) Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 13:2140–2144PubMedCrossRefGoogle Scholar
  12. 12.
    Robert S, Zarowitz BJ, Peterson EL, Dumler F (1993) Predictability of creatinine clearance estimates in critically ill patients. Crit Care Med 21:1487–1495PubMedCrossRefGoogle Scholar
  13. 13.
    Kirkpatrick CM, Duffull SB, Begg EJ (1999) Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. Br J Clin Pharmacol 47:637–643PubMedCrossRefGoogle Scholar
  14. 14.
    Aronson JK (2007) Drug therapy in kidney diesease. Br J Clin Pharmacol 63:509–511PubMedCrossRefGoogle Scholar
  15. 15.
    Herget-Rosenthal S, Bökenkamp A, Hofmann W (2007) How to estimate GFR—serum creatinine, serum cystatin C or equations? Clin Biochem 40:153–161PubMedCrossRefGoogle Scholar
  16. 16.
    Filler G, Bökenkamp A, Hofmann W, Lebricon T, Martinez-Bru C, Grubb A (2005) Cystatin C as a marker of GFR—history, indications, and future research. Clin Biochem 38:1–8PubMedCrossRefGoogle Scholar
  17. 17.
    Work DF, Schwartz GJ (2008) Estimating and measuring glomerular filtration rate in children. Curr Opin Nephrol Hypertens 17:320–325PubMedCrossRefGoogle Scholar
  18. 18.
    Proulx NL, Akbari A, Garg AX, Rostom A, Jaffey J, Clark HD (2005) Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis. Nephrol Dial Transplant 20:1617–1622PubMedCrossRefGoogle Scholar
  19. 19.
    Waller DG (2007) Drugs and the kidney: more than a question of dose. Br J Clin Pharmacol 64:719–721PubMedCrossRefGoogle Scholar
  20. 20.
    Sica DA (2007) Considerations in drug handling in renal disease. Clin Pharmacokinet 46:677–679PubMedCrossRefGoogle Scholar
  21. 21.
    Fuhr A, Jetter A, Kirchheiner J (2007) Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the „cocktail“ approach. Clin Pharmacol Ther 81:270–283PubMedCrossRefGoogle Scholar
  22. 22.
    Gross AS, MacLachlan AJ, Minns I et al (2001) Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol. Br J Clin Pharmacol 51:547–555PubMedCrossRefGoogle Scholar
  23. 23.
    Tozer TN, Rowland M (2006) Introduction to pharmacokinetics and pharmacodynamics: the quantitative basis of drug therapy. Lippincott Williams & Williams, Philadelphia, pp 97–100Google Scholar
  24. 24.
    Lee W, Kim B (2004) Transporters and renal elimination. Annu Rev Pharmacol Toxicol 44:137–166PubMedCrossRefGoogle Scholar
  25. 25.
    El-Sheikh AAK, Masereeuw R, Russel FGM (2008) Mechanisms of renal anionic transport. Eur J Pharmacol 585:245–255PubMedCrossRefGoogle Scholar
  26. 26.
    Koepell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251CrossRefGoogle Scholar
  27. 27.
    Wilkinson GR (1987) Clearance approaches in pharmacology. Pharmacol Rev 39:1–47PubMedGoogle Scholar
  28. 28.
    Baumann A (2006) Early development of therapeutic biologics—pharmacokinetics. Curr Drug Metab 7:15–21PubMedCrossRefGoogle Scholar
  29. 29.
    Mahmood I, Green MD (2005) Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin Pharmacokinet 44:331–347PubMedCrossRefGoogle Scholar
  30. 30.
    Daniel H, Rubio-Aliaga I (2003) An update on renal peptide transporters. Am J Renal Physiol 284:F885–F892Google Scholar
  31. 31.
    Braeckman R (2000) Pharmacokinetics and pharmacodynamics of protein therapeutics. In: Reid ER (ed) Peptides and protein drug analysis. Marcel Dekker, New York, pp 633–649Google Scholar
  32. 32.
    Rowland M, Tozer TN (1995) Clinical pharmacokinetics: concepts and applications, 3rd edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  33. 33.
    Lam YWF, Banerji S, Hatfield C, Talbert RL (1997) Principles of drug administration in renal insufficiency. Clin Pharmacokinet 32:30–57PubMedCrossRefGoogle Scholar
  34. 34.
    Matzke GR, Comstock TJ (2006) Influence of renal function and dialysis on drug disposition. In: Burton ME, Shaw LM, Schentag JJ, Evans WE (eds) Applied pharmacokinetics and pharmacodynamics: principles of therapeutic drug monitoring, 4th edn. Lippincott Williams & Wilkins, Philadelphia, pp 187–212Google Scholar
  35. 35.
    Gibson TP, Giacomini KM, Briggs WA et al (1980) Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient. Clin Pharmacol Ther 27:665–670PubMedGoogle Scholar
  36. 36.
    Levy G, Giacomini KM (1981) First-pass effects in health and disease: pharmacokinetics studies on dextropropoxyphene. In: Prescott LF, Nimmo WS (eds) Drug absorption: Proc Edinburgh Int Conf. MTP Press, Lancaster pp 115–122Google Scholar
  37. 37.
    Bianchetti G, Graziani G, Brancacci D et al (1976) Pharmacokinetics and effects of propranolol in terminal uremic patients and in patients undergoing regular dialysis treatment. Clin Pharmacokinet 1:373–384PubMedCrossRefGoogle Scholar
  38. 38.
    Davies G, Kingswood C, Street M (1996) Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacokinet 31:410–422PubMedCrossRefGoogle Scholar
  39. 39.
    Muirhead GJ, Wilner K, Colburn W, Haug-Pihale G, Rouvieux B (2002) The effect of age and renal and hepatic impairment on the Pharmacokinetics of sildenafil citrate. Br J Clin Pharmacol 53:21S–30SPubMedCrossRefGoogle Scholar
  40. 40.
    Kays MB, Overholser BR, Mueller BA et al (2003) Effects of sevelamer hydrochloride and calcium acetate on the oral bioavailability of ciprofloxacin. Am J Kidney Dis 42:1253–1259PubMedCrossRefGoogle Scholar
  41. 41.
    How PP, Fischer JH, Arruda JA et al (2007) Effects of lanthanum carbonate on the absorption and oral bioavailability of ciprofloxacin. Clin J Am Soc Nephrol 2:1235–1240PubMedCrossRefGoogle Scholar
  42. 42.
    MacKichan JJ (2006) Influence of protein binding and use of unbound (free) drug concentrations. In: Burton ME, Shaw LM, Schentag JJ, Evans WE (eds) Applied pharmacokinetics and pharmacodynamics—principles of therapeutic drug monitoring. Lippincott Williams, Wilkins, Philadelphia, pp 82–120Google Scholar
  43. 43.
    Bricker NS, Morrin PAF, Kime SW Jr (1997) The pathologic physiology of chronic Bright’s Disease: an exposition of the “intact nephron hypothesis”. J Am Soc Nephrol 8:1470–1476PubMedGoogle Scholar
  44. 44.
    Periclou A, Ventura D, Niranjan R, Abramowitz W (2006) Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther 79:134–143PubMedCrossRefGoogle Scholar
  45. 45.
    Balant LP, Dayer P, Fabre J (1983) Consequences of renal insufficiency on the hepatic clearance of some drugs. Int J Clin Pharmacol Res 3:459–474PubMedGoogle Scholar
  46. 46.
    Gibson TP (1986) Renal disease and drug metabolism. Am J Kidney Dis 8:7–17PubMedGoogle Scholar
  47. 47.
    Elston AC, Bayliss MK, Park GR (1993) Effect of renal failure on drug metabolism. Br J Anaesth 71:282–290PubMedCrossRefGoogle Scholar
  48. 48.
    Dowling TC, Briglia AE, Fink JC, Hanes DS, Light PD, Stackiewicz L, Karyekar CS, Eddington ND, Weir MR, Henrich WL (2003) Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther 73:427–434PubMedCrossRefGoogle Scholar
  49. 49.
    Frassetto LA, Poon S, Tsourounis C, Valera C, Benet LZ (2007) Effects of uptake and efflux transporter inhibition on erythromycin breath test results. Clin Pharmacol Ther 81:828–832PubMedCrossRefGoogle Scholar
  50. 50.
    Dreisbach AW, Japa S, Gebrekal AB, Mowry SE, Lertora JJL, Kamath BL, Rettie AE (2003) Cytochrome P4502C9 activity in end-stage renal disease. Clin Pharmacol Ther 73:475–477 Letter to the EditorPubMedCrossRefGoogle Scholar
  51. 51.
    Stehle S, Kirchheiner J, Lazar A, Fuhr U (2008) Pharmacogenetics of oral anticoagulants—a basis for dose individualization. Clin Pharmacokinet 47:565–594PubMedCrossRefGoogle Scholar
  52. 52.
    Frye RF et al (2006) Liver disease Selectivey modulates cytochrome P450- mediated metabolism drugs in liver. Clin Pharmacol Ther 80:235–245PubMedCrossRefGoogle Scholar
  53. 53.
    Verbeeck RK (2008) Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 64:1147–1161Google Scholar
  54. 54.
    Teunissen MWE, Kampf D, Roots I et al (1985) Antipyrine metabolite formation and excretion in patients with chronic renal insufficiency. Eur J Clin Pharmacol 28:589–595PubMedCrossRefGoogle Scholar
  55. 55.
    Leblond FA, Giroux L, Villeneuve JP, Pichette V (2000) Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Disp 28:1317–1320Google Scholar
  56. 56.
    Leblond F, Guévin C, Demers C, Pellerin I, Gascon-Barré M, Pichette V (2001) Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol 12:326–332PubMedGoogle Scholar
  57. 57.
    Leblond FA, Petrucci M, Dubé P, Bernier G, Bonnardeaux A, Pichette V (2002) Downregulation of intestinal cytochrome P450 in chronic renal failure. J Am Soc Nephrol 13:1579–1585PubMedCrossRefGoogle Scholar
  58. 58.
    Guévin C, Michaud J, Naud J, Leblond FA, Pichette V (2002) Down-regulation of hepatic cytochrome P450 in chronic renal failure: the role of uremic mediators. Br J Pharmacol 137:1039–1046PubMedCrossRefGoogle Scholar
  59. 59.
    Pichette V, Leblond FA (2003) Drug metabolism in chronic renal failure. Curr Drug Metab 4:91–103PubMedCrossRefGoogle Scholar
  60. 60.
    Sun H, Huang Y, Frassetto L, Benet LZ (2004) Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Disp 32:1239–1246CrossRefGoogle Scholar
  61. 61.
    Michaud J, Dubé P, Naud J, Leblond FA, Desbiens K, Bonnardeaux A, Pichette V (2005) Effects of serum from patients with chronic renal failure on rat heaptic cytochrome P450. Br J Pharmacol 144:1067–1077PubMedCrossRefGoogle Scholar
  62. 62.
    Sun H, Frassetto L, Benet LZ (2006) Effects of renal failure on drug transport and metabolism. Pharmacol Ther 109:1–11PubMedCrossRefGoogle Scholar
  63. 63.
    Michaud J, Naud J, Chouinard J, Désy F, Leblond FA, Desbiens K, Bonnardeaux A, Pichette V (2006) Role of parathyroid hormone in the down-regulation of liver cytochrome P450 in chronic renal failure. J A Soc Nephrol 17:3041–3048CrossRefGoogle Scholar
  64. 64.
    Nolin TD, Naud J, Leblond FA, Pichette V (2008) Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther 83:898–903PubMedCrossRefGoogle Scholar
  65. 65.
    Simard E, Naud J, Michaud J, Leblond FA, Bonnardeaux A, Guillemette C, Sim E, Pichette V (2008) Downregulation of hepatic acetylation of drugs in chronic renal failure. J Am Soc Nephrol 19:1352–1359PubMedCrossRefGoogle Scholar
  66. 66.
    Yu C, Ritter JK, Krieg RJ, Rege B, Karnes TH, Sarkar MA (2006) Effect of chronic renal insufficiency on hepatic and renal UDP- glucuronyltransferases in rats. Drug Metab Disp 34:621–627CrossRefGoogle Scholar
  67. 67.
    Nolin TD, Appiah K, Kendrick SA, Le P, McMonagle E, Himmelfarb J (2006) Hemodialysis acutely improves hepatic CYP3A4 metabolic activity. J Am Soc Nephrol 17:2363–2367PubMedCrossRefGoogle Scholar
  68. 68.
    Miners JO, Mackenzie PI (1991) Drug glucuronidation in humans. Pharmacol Ther 51:347–369PubMedCrossRefGoogle Scholar
  69. 69.
    Bailey MJ, Dickinson RG (2003) Acyl glucuronide reactivity in perspective: biological consequences. Chem Biol Interact 145:117–137PubMedCrossRefGoogle Scholar
  70. 70.
    Verbeeck RK (1982) Glucuronidation and disposition of drug glucuronides in patients with renal failure. Drug Metab Disp 10:87–89Google Scholar
  71. 71.
    Stafanger G, Larson HW, Hansen H, Sorensen K (1981) Pharmacokinetics of ketoprofen in patients with chronic renal failure. Scand J Rheumatol 10:189–192PubMedCrossRefGoogle Scholar
  72. 72.
    Skeith KJ, Dasgupta M, Lange R, Jamali F (1996) The influence of renal function on the pharmacokinetics of unchanged and acyl- glucuronide ketoprofen enantiomers after 50 and 100 mg racemic ketoprofen. Br J Clin Pharmacol 42:163–169PubMedCrossRefGoogle Scholar
  73. 73.
    Grubb NG, Rudy DW, Brater DC, Hall SD (1999) Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end-stage renal disease: evidence for a ‘futile cycle’ of elimination. Br J Clin Pharmacol 48:494–500PubMedCrossRefGoogle Scholar
  74. 74.
    Yue QY, Odar-Cederlöf I, Svensson JO, Säwe J (1988) Glucuronidation of morphine in human kidney microsomes. Pharmacol Toxicol 63:337–341PubMedCrossRefGoogle Scholar
  75. 75.
    Raoof AA, Van Obbergh LJ, de Ville de Goyet J, Verbeeck RK (1996) Extrahepatic metabolism of propofol in man: possible contribution of gut wall and kidney. Eur J Clin Pharmacol 50:91–96PubMedCrossRefGoogle Scholar
  76. 76.
    McGurk KA, Brierley CH, Burchell B (1998) Drug glucuronidation by human reanl UDP-glucuronosyltransferases. Biochem Pharmacol 55:1005–1012PubMedCrossRefGoogle Scholar
  77. 77.
    Mazoit JX, Sandouk P, Scherrmann JM, Roche A (1990) Extrahepatic metabolism of morphine occurs in humans. Clin Pharmacol Ther 48:613–618PubMedGoogle Scholar
  78. 78.
    Vree TB, Hekster YA, Anderson PG (1992) Contribution of the human kidney to the metabolic clearance of drugs. Ann Pharmacother 26:1421–1428PubMedGoogle Scholar
  79. 79.
    Hiraoka H, Yamamoto K, Miyoshi S, Morita T, Nakamura K, Kadoi Y, Kunimoto F, Horiuchi R (2005) Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain. Br J Clin Pharmacol 60:176–182PubMedCrossRefGoogle Scholar
  80. 80.
    Verpooten GA, Verbist L, Buntinx AP, Entwistle LA, Jones KH, De Broe ME (1984) The pharmacokinetics of imipenem (thienamycin- formamidine) and the renal dehydropeptidase inhibitor cilastin sodium in normal subjects and patients with renal failure. Br J Clin Pharmacol 18:183–193PubMedGoogle Scholar
  81. 81.
    Ho RH, Kim RB (2005) Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 78:260–277PubMedCrossRefGoogle Scholar
  82. 82.
    Benet LZ, Cummins CL, Wu CY (2003) Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab 4:393–398PubMedCrossRefGoogle Scholar
  83. 83.
    Wu CY, Benet LZ (2005) Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22:11–23PubMedCrossRefGoogle Scholar
  84. 84.
    Lam JL, Okochi H, Huanh Y, Benet LZ (2006) In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism characterizing the importance of transporter-enzyme interplay. Drug Metab Disp 34:1336–1344CrossRefGoogle Scholar
  85. 85.
    Lau YY, Huang Y, Frassetto L, Benet LZ (2007) Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther 81:194–204PubMedCrossRefGoogle Scholar
  86. 86.
    Naud J, Michaud J, Boisvert C, Desbiens K, Leblod FA, Mitchell A, Jones C, Bonnardeaux A, Pichette V (2007) Down-regulation of intestinal drug transporters in chronic renal failure in rats. J Pharmacol Exp Ther 320:978–985PubMedCrossRefGoogle Scholar
  87. 87.
    Naud J, Michaud J, Leblond FA, Lefrancois S, Bonnardeaux A, Pichette V (2008) Effects of chronic renal failure on liver drug transporters. Drug Metab Disp 36:124–128CrossRefGoogle Scholar
  88. 88.
    Niwa T, Miyazaki T, Katsuzaki T, Tatemichi N, Takei Y (1996) Serum levels of 3-deoxyglucosoneand tissue contents of advanced glycation end-products are increased in streptozotocin-induced diabetic rats with nephropathy. Nephron 74:580–585PubMedCrossRefGoogle Scholar
  89. 89.
    Dzurik R, Spustova V, Krivosikova Z, Gazdikova K (2001) Hippurate participates in the correction of metabolic acidosis. Kidney Int Suppl 78:S278–S281PubMedCrossRefGoogle Scholar
  90. 90.
    Gusella M, Rebeschini M, Cartel G, Ferrazzi E, Ferrari M, Padrini R (2005) Effect of hemodialysis on the metabolic clearance of 5-fluorouracil in a patient with end-stage renal failure. Ther Drug Monit 27:816–818PubMedCrossRefGoogle Scholar
  91. 91.
    Michaud J, Nolin TD, Naud J, Dani M, Lafrance JP, Leblond FA, Himmelfarb J and Pichette V (2008) Effect of hemodialysis on hepatic Cytochrome P450 functional expression. J Pharmacol Sci 108(2):157–163Google Scholar
  92. 92.
    Verbeeck RK, Branch RA, Wilkinson GR (1981) Drug metabolites in renal failure: pharmacokinetics and clinical implications. Clin Pharmacokinet 6:329–345PubMedCrossRefGoogle Scholar
  93. 93.
    McQuay H, Moore A (1984) Be aware of renal function when prescribing morphine. Lancet ii:284–285CrossRefGoogle Scholar
  94. 94.
    Osborne R, Joel SP, Slevin ML (1986) Morphine intoxication in renal insufficiency: the role of morphine-6-glucuronide. Br Med J 292:1548–1549CrossRefGoogle Scholar
  95. 95.
    Säwe J, Odar-Cederlöf I (1987) Kinetics of morphine in patients with renal failure. Eur J Clin Pharmacol 32:377–382PubMedCrossRefGoogle Scholar
  96. 96.
    Osborne R, Joel S, Grebenik K, Trew D, Slevin M (1993) The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 54:158–167PubMedGoogle Scholar
  97. 97.
    Pasternak GW, Bodnar RJ, Clark JA, Interrusi CE (1987) Morphine-6-glucuronide, a potent mu agonist. Life Sci 41:2845–2849PubMedCrossRefGoogle Scholar
  98. 98.
    Penson RT, Joel SP, Bakhshi K, Clark SJ, Langford RM, Slevin ML (2000) Randomized placebo-controlled trial of activity of the morphine glucuronides. Clin Pharmacol Ther 68:667–676PubMedCrossRefGoogle Scholar
  99. 99.
    Penson RT, Joel SP, Gloyne A, Clark S, Slevin ML (2005) Morphine analgesia in cancer pain: role of the glucuronides. J Opioid Manag 1:83–90PubMedGoogle Scholar
  100. 100.
    Dale O, Thoner J, Nilsen T, Tveita T, Borchgrevink PC, Klepstad P (2007) Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery. Eur J Clin Pharmacol 63:837–842PubMedCrossRefGoogle Scholar
  101. 101.
    D’Honneur G, Gilton A, Sandouk P, Scherrmann JM, Duvaldestin P (1994) Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morhine. Anesthesiology 81:87–93PubMedCrossRefGoogle Scholar
  102. 102.
    Lötsch J, Schmidt R, Vetter G, Schmidt H, Niederberger E, Geisslinger G, Tegeder I (2002) Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein. J Neurochem 83:241–248PubMedCrossRefGoogle Scholar
  103. 103.
    Bourasset F, Cisternino S, Temsamani J, Scherrmann JM (2003) Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain-barrier. J Neurochem 86:1564–1567PubMedCrossRefGoogle Scholar
  104. 104.
    Lötsch J, Zimmermann M, Darimont J, Marx C, Dudziak R, Skarke C, Geisslinger G (2002) Does the A118G polymorphism at the µ-opioid receptor gene protect against morphine-6-glucuronide toxicity? Anesthesiology 97:814–819PubMedCrossRefGoogle Scholar
  105. 105.
    Woffindin C, Hoenich NA (1995) Hemodialyzer performance: a review of the trends over the past two decades. Artif Organs 19:1113–1119PubMedCrossRefGoogle Scholar
  106. 106.
    Gjessing J (2008) Studies on peritoneal dialysis. Kidney Int Suppl 108:S18–S25PubMedCrossRefGoogle Scholar
  107. 107.
    Fujimura T, Uchi Y, Fukuda M, Miyazaki M, Uezumi S, Hiyoshi T (2004) Development of a dialyzer with enhanced internal filtration to increase the clearance of low molecular weight proteins. J Artif Organs 7:149–153PubMedCrossRefGoogle Scholar
  108. 108.
    Lucchi L, Fiore GB, Guadagni G, Perrone S, Malaguti V, Caruso F, Fumero R, Albertazzi A (2004) Clinical evaluation of internal hemodiafiltration (iHDF): a diffusive-convective technique performed with internal filtration enhanced high-fluc dialyzers. Int J Artif Organs 27:414–419PubMedGoogle Scholar
  109. 109.
    FDA Guidance for Industry (1998) Pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labelling. Available at:
  110. 110.
    EMEA (2004) Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function. Available at:
  111. 111.
    Golper TA, Marx MA, Shuler C et al (1996) Drug dosage in dialysis patients. In: Jacobs C, Kjellstrand CM, Koch KM (eds) Replacement of Renal Function by Dialysis. Kluwer, Boston, pp 750–614CrossRefGoogle Scholar
  112. 112.
    Aronoff GR, Bennett WM, Berns JS et al (2007) DrugpPrescribing in renal failure: dosing guidelines for adults and children, 5th edn. American College of Physicians, PhiladelphiaGoogle Scholar
  113. 113.
    Asari A, Iles-Smith H, Chen Y-C, Naderer O, Johnson MA, Yuen GJ, Otto V, Dunn JA, Gokal R (2007) Pharmacokinetics of lamivudine in subjects receiving peritoneal dialysis in end-stage renal failure. Br J Clin Pharmacol 64:738–744PubMedGoogle Scholar
  114. 114.
    Decker BS, Mueller BA, Sowinski KM (2007) Drug dosing considerations in alternative hemodialysis. Adv Chronic Kidney Dis 14:17–26CrossRefGoogle Scholar
  115. 115.
    Sowinski KM, Magner SJ, Lucksiri A, Scott MK, Hamburger MJ, Mueller BA (2008) Influence of hemodialysis on gentamicin pharmacokinetics, removal during hemodialysis, and recommended dosing. Clin J Am Soc Nephrol 3:355–361PubMedCrossRefGoogle Scholar
  116. 116.
    Ponto LL, Schoenwald RD (1990) Furosemide (frusemide): a pharmacokinetic/pharmacodynamic review (part I). Clin Pharmacokinet 18:381–408PubMedCrossRefGoogle Scholar
  117. 117.
    Brater DC, Anderson SA, Brown-Cartwright D (1986) Response to furosemide in chronic renal insufficiency: rationale for limited doses. Clin Pharmacol Ther 40:134–139PubMedGoogle Scholar
  118. 118.
    Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX (2002) Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 105:225–231PubMedCrossRefGoogle Scholar
  119. 119.
    Hulot JS, Vantelon C, Urien S, Bouzamondo A, Mahé I, Ankri A, Montalescot G, Lechat P (2004) Effect of renal failure on the pharmacokinetics of enoxaparin and consequences on dose adjustment. Ther Drug Monit 26:305–310PubMedCrossRefGoogle Scholar
  120. 120.
    Noris M, Remuzzi G (1999) Uremic bleeding: closing the circle after 30 years of controversies? Blood 94:2569–2574PubMedGoogle Scholar
  121. 121.
    Fischer KG (2007) Essentials of anticoagulation in hemodialysis. Hemodial Int 11:178–189PubMedCrossRefGoogle Scholar
  122. 122.
    Brophy DF, Sica DA (2007) Use of enoxaparin in patients with chronic kidney disease: safety considerations. Drug Saf 30:991–994PubMedCrossRefGoogle Scholar
  123. 123.
    Fareed J, Hoppensteadt D, Walnga J, Iqbal O, Ma Q, Jeske W, Sheikh T (2003) Pharmacodynamic and harmacokinetic properties of enoxaparin: implications for clinical practice. Clin Pharmacokinet 42:1043–1057PubMedCrossRefGoogle Scholar
  124. 124.
    Edholm M, Berglund EG, Salmonson T (2008) Regulatory aspects of pharmacokinetic profiling in special populations. Clin Pharmacokinet 48:693–701CrossRefGoogle Scholar
  125. 125.
    Zhang Y, Zhang L, Abraham S, Apparaju S, Wu T-C, Strong JM, Xiao S, Atkinson AJ Jr, Thummel KE, Leeder JS, Lee C, Burckart GJ, Lesko LJ, Huang S-M (2009) Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications. Clin Pharmacol Ther 85:305–311PubMedCrossRefGoogle Scholar
  126. 126.
    Peck C, Barr W, Benet L et al (1992) Opportunities for integration of pharmacokinetics, pharmacodynamics and toxicokinetics in rational drug development. Clin Pharmacol Ther 51:465–473PubMedGoogle Scholar
  127. 127.
    Aarons L, Balant LP, Mentré F et al (1994) Population approaches in drug development: report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software. Eur J Clin Pharmacol 46:389–391PubMedCrossRefGoogle Scholar
  128. 128.
    FDA Guidance for Industry (1999) Population pharmacokinetics. Available at:
  129. 129.
    Toublanc N, Sargentini-Maier ML, Lacroix B, Jacqmin P, Stockis A (2008) Retrospective population pharmacokinetic analysis of levetiracetam in children and adolescents with epilepsy: dosing recommendations. Clin Pharmacokinet 47:333–341PubMedCrossRefGoogle Scholar
  130. 130.
    Zandvliet AS, Schellens JHM, Beijnen JH, Huitema ADR (2008) Population pharmacokinetics and pharmacodynamics for treatment optimization in clinical oncology. Clin Pharmacokinet 47:487–513PubMedCrossRefGoogle Scholar
  131. 131.
    Tzeng TB, Schneck DW, Birmingham BK, Mitchell PD, Zhang H, Martin PD, Kung LP (2008) Population pharmacokinetics of rosuvastatin: implications of renal impairment, race and dyslipidaemias. Curr Med Res Opin 24:2575–2585PubMedCrossRefGoogle Scholar
  132. 132.
    Food and Drug Administration (2004) Enoxaparin injection drug approval. Available at:
  133. 133.
    Hulot J-S, Montalescot G, Lechat P, Collet J-P, Ankri A, Urien S (2005) Dosing strategy in patients with renal failure receiving enoxaparin for the treatment of non-ST-segment elevation acute coronary syndrome. Clin Pharmacol Ther 77:542–552PubMedCrossRefGoogle Scholar
  134. 134.
    Vidal L, Shavit M, Fraser A, Paul M, Leibovici L (2005) Systematic comparison of four sources of drug information regarding adjustment of dose for renal function. Br Med J 331:263–266CrossRefGoogle Scholar
  135. 135.
    Committee JF (2004) British national formulary, 48th edn. London, British Medical Association and Royal Pharmaceutical Society of Great Britain, LondonGoogle Scholar
  136. 136.
    Sweetman SC (ed) (2004) Martindale; the complete drug reference. Pharmaceutical Press, LondonGoogle Scholar
  137. 137.
    McEvoy GK, Miller J, Snow EK, Welsh OH, Litvak K (eds) (2004) American hospital (AHFS) drug information. American Society of Health-System Pharmacists, BethesdaGoogle Scholar
  138. 138.
    Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G, Singer I et al (eds) (1999) Drug prescribing in renal failure: dosing guidelines for adults (1999) American College of Physicians, PhiladelphiaGoogle Scholar
  139. 139.
    Letters to the Editor (2005) Dose adjustment in renal impairment. Br Med J 331:292–294Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Faculty of PharmacyRhodes UniversityGrahamstownSouth Africa
  2. 2.School of PharmacyCatholic University of LouvainLouvainBelgium

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