Clinical Pharmacokinetics

, Volume 47, Issue 5, pp 297–321 | Cite as

Free Drug Metabolic Clearance in Elderly People

  • Jennifer M. Butler
  • Evan J. Begg
Review Article


The question of whether metabolic drug clearance is decreased in elderly people has been the subject of considerable debate and is very important because clearance is a determinant of dosing. Drug clearance has been shown to be consistently impaired for flow-limited (high-clearance) drugs, but there have been conflicting results for capacity-limited (low-clearance) drugs. A limitation of the studies of capacity-limited drugs is that most have estimated clearance based on total drug concentrations (protein-bound plus free). Total drug clearance reflects both the intrinsic clearance of free drug and the extent of protein binding. Total clearance is a valid measure for capacity-limited drugs with low protein binding and appears to be consistently impaired in elderly subjects. For phenazone [antipyrine] (fraction unbound [fu] >0.9), seven studies have demonstrated statistical reductions in clearance of 20–52%. For theophylline (fu 0.6), five studies have demonstrated reductions in clearance of 22–35%. For paracetamol [acetaminophen] (fu 0.8), the clearance of which has been quoted as unchanged, four studies have demonstrated reductions in clearance of 19–35%. For highly protein-bound drugs, total clearance is not the appropriate parameter. Free drug clearance is more appropriate since it is independent of changes in protein binding. The literature was reviewed to test the hypothesis that in elderly people, capacity-limited drugs with high protein binding will show decreased free clearance even in the absence of a decrease in total clearance. For these drugs, data for free drug clearance based on measurement of actual free drug concentrations are limited, but suggest that the intrinsic metabolic clearance is impaired in elderly subjects. Four studies of naproxen (fu <0.01) have shown reduced free drug clearance of 50% or more. Two studies of valproic acid (fu 0.1–0.2) have shown reduced free clearance of 39% and 65%. Two studies of ibuprofen (fu <0.01) have shown reduced free clearance of S-ibuprofen of 21% and 28%. There is some indirect evidence for reduced clearance of the highly protein-bound drugs oxaprozin, temazepam, lorazepam, diazepam, phenytoin and warfarin, although studies measuring free concentrations are lacking. Together, the above studies support the hypothesis that the intrinsic metabolic drug clearance is impaired in elderly subjects, in the order of 20–60%, and that this effect is masked if highly protein-bound drugs are assessed using total drug clearance. If the findings are confirmed in future well-designed studies of free drug clearance, there are profound and beneficial implications for dosing of drugs in elderly people. Lower doses are likely to achieve appropriate concentrations, allowing full efficacy but decreased dose-related adverse effects.


Naproxen Free Fraction Total Clearance Intrinsic Clearance Free Drug Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors wish to thank Mrs Petra Shepard (Personal Assistant, Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand) for assistance with the presentation/layout of the article (in particular, the tables). No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Durnas C, Loi CM, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet 1990; 19(5): 359–89PubMedCrossRefGoogle Scholar
  2. 2.
    LeCouteur DG, McLean AJ. The aging liver: drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet 1998; 34(5): 359–73PubMedCrossRefGoogle Scholar
  3. 3.
    Susla GM, Atkinson AJ. Effect of liver disease on pharmacokinetics. In: Atkinson AJ, Daniels CE, Dedrick RL, et al., editors. Principles of clinical pharmacology. New York: Academic Press: 2001: 63–74Google Scholar
  4. 4.
    Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71(3): 115–21PubMedCrossRefGoogle Scholar
  5. 5.
    Aggeler PM, O’Reilly RA, Leong L, et al. Potentiation of anticoagulant effect of warfarin by phenylbutazone. N Engl J Med 1967; 276(9): 496–501PubMedCrossRefGoogle Scholar
  6. 6.
    Levy RH, Moreland TA. Rationale for monitoring free drug levels. Clin Pharmacokinet 1984; 9 Suppl. 1: 1–9PubMedCrossRefGoogle Scholar
  7. 7.
    Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet 2000; 38(3): 271–90PubMedCrossRefGoogle Scholar
  8. 8.
    Dawling S, Crome P. Clinical pharmacokinetic considerations in the elderly: an update. Clin Pharmacokinet 1989; 17(4): 236–63PubMedCrossRefGoogle Scholar
  9. 9.
    McLean AJ, LeCouteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56(2): 163–84PubMedCrossRefGoogle Scholar
  10. 10.
    Massoud N. Pharmacokinetic considerations in geriatric patients. In: Benet LZ, editor. Pharmacokinetic basis for drug treatment. New York: Raven Press, 1984: 283–307Google Scholar
  11. 11.
    Wynne HA, Cope LH, Herd B, et al. The association of age and frailty with paracetamol conjugation in man. Age Ageing 1990; 19(6): 419–24PubMedCrossRefGoogle Scholar
  12. 12.
    Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging 2001; 18(11): 837–51PubMedCrossRefGoogle Scholar
  13. 13.
    Bach B, Molholm Hansen J, Kampmann JP, et al. Disposition of antipyrine and phenytoin correlated with age and liver volume in man. Clin Pharmacokinet 1981; 6(5): 389–96PubMedCrossRefGoogle Scholar
  14. 14.
    Swift CG, Ewen JM, Clarke P, et al. Responsiveness to oral diazepam in the elderly: relationship to total and free plasma concentrations. Br J Clin Pharmacol 1985; 20(2): 111–8PubMedCrossRefGoogle Scholar
  15. 15.
    Schulz P, Turner-Tamiyasu K, Smith G, et al. Amitriptyline disposition in young and elderly normal men. Clin Pharmacol Ther 1983; 33(3): 360–6PubMedCrossRefGoogle Scholar
  16. 16.
    Ogura C, Kishimoto A, Mizukawa R, et al. Age differences in effects on blood pressure, flicker fusion frequency, salivation and pharmacokinetics of single oral doses of dothiepin and amitriptyline. Eur J Clin Pharmacol 1983; 25(6): 811–4PubMedCrossRefGoogle Scholar
  17. 17.
    Nation RL, Learoyd B, Barber J, et al. The pharmacokinetics of chlormethiazole following intravenous administration in the aged. Eur J Clin Pharmacol 1976; 10(6): 407–15PubMedCrossRefGoogle Scholar
  18. 18.
    Nation RL, Vine J, Triggs EJ, et al. Plasma level of chlormethiazole and two metabolites after oral administration to young and aged human subjects. Eur J Clin Pharmacol 1977; 12(2): 137–45PubMedCrossRefGoogle Scholar
  19. 19.
    Abernethy DR, Greenblatt DJ, Shader RI. Imipramine and desipramine disposition in the elderly. J Pharmacol Exp Ther 1985; 232(1): 183–8PubMedGoogle Scholar
  20. 20.
    Montamat SC, Abernethy DR. Calcium antagonists in geriatric patients: diltiazem in elderly persons with hypertension. Clin Pharmacol Ther 1989; 45(6): 682–91PubMedCrossRefGoogle Scholar
  21. 21.
    Schwartz JB, Abernethy DR. Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension. Am J Cardiol 1987; 59(12): 1111–7PubMedCrossRefGoogle Scholar
  22. 22.
    Bentley JB, Borel JD, Nenad RE, et al. Age and fentanyl pharmacokinetics. Anesth Analg 1982; 61(12): 968–71PubMedCrossRefGoogle Scholar
  23. 23.
    Singleton MA, Rosen JI, Fisher DM. Pharmacokinetics of fentanyl in the elderly. Br J Anaesth 1988; 60(6): 619–22PubMedCrossRefGoogle Scholar
  24. 24.
    Abernethy DR, Schwartz JB, Plachetka JR, et al. Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension. Am J Cardiol 1987; 60(8): 697–702PubMedCrossRefGoogle Scholar
  25. 25.
    Rocci Jr ML, Vlasses PH, Cressman MD, et al. Pharmacodynamics and disposition of labetalol in elderly vs young hypertensives [abstract]. Clin Pharmacol Ther 1987; 41: 171Google Scholar
  26. 26.
    Robertson DR, Wood ND, Everest H, et al. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol 1989; 28(1): 61–9PubMedCrossRefGoogle Scholar
  27. 27.
    Nation RL, Triggs EJ, Selig M. Lignocaine kinetics in cardiac patients and aged subjects. Br J Clin Pharmacol 1977; 4(4): 439–48PubMedCrossRefGoogle Scholar
  28. 28.
    Abernethy DR, Greenblatt DJ. Impairment of lidocaine clearance in elderly male subjects. J Cardiovasc Pharmacol 1983; 5(6): 1093–6PubMedCrossRefGoogle Scholar
  29. 29.
    Cusack B, O’Malley K, Lavan J, et al. Protein binding and disposition of lignocaine in the elderly. Eur J Clin Pharmacol 1985; 29(3): 323–9PubMedCrossRefGoogle Scholar
  30. 30.
    Murray GR, Franklin RA, Graham DF, et al. Pharmacokinetics of meptazinol after parenteral administration. Eur J Clin Pharmacol 1987; 31(6): 733–6PubMedCrossRefGoogle Scholar
  31. 31.
    Larsson M, Landahl S, Lundborg P, et al. Pharmacokinetics of metoprolol in healthy, elderly, non-smoking individuals after a single dose and two weeks of treatment. Eur J Clin Pharmacol 1984; 27(2): 217–22PubMedCrossRefGoogle Scholar
  32. 32.
    Owen JA, Sitar DS, Berger L, et al. Age-related morphine kinetics. Clin Pharmacol Ther 1983; 34(3): 364–8PubMedCrossRefGoogle Scholar
  33. 33.
    Baillie SP, Bateman DN, Coates PE, et al. Age and the pharmacokinetics of morphine. Age Ageing 1989; 18(4): 258–62PubMedCrossRefGoogle Scholar
  34. 34.
    Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of intravenous and intramuscular morphine. Clin Pharmacol Ther 1978; 24(1): 52–9PubMedGoogle Scholar
  35. 35.
    Jaillon P, Gardin ME, Lecocq B, et al. Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients. Clin Pharmacol Ther 1989; 46(2): 226–33PubMedCrossRefGoogle Scholar
  36. 36.
    Dawling S, Crome P, Braithwaite R. Pharmacokinetics of single oral doses of nortriptyline in depressed elderly hospital patients and young healthy volunteers. Clin Pharmacokinet 1980; 5(4): 394–401PubMedCrossRefGoogle Scholar
  37. 37.
    Holmberg L, Odar-Cederlöf I, Boréus LO, et al. Comparative disposition of pethidine and norpethidine in old and young patients. Eur J Clin Pharmacol 1982; 22(2): 175–9PubMedCrossRefGoogle Scholar
  38. 38.
    Herman RJ, McAllister CB, Branch RA, et al. Effects of age on meperidine disposition. Clin Pharmacol Ther 1985; 37(1): 19–24PubMedCrossRefGoogle Scholar
  39. 39.
    Kirkpatrick T, Cockshott ID, Douglas EJ, et al. Pharmacokinetics of propofol (diprivan) in elderly patients. Br J Anaesth 1988; 60(2): 146–50PubMedCrossRefGoogle Scholar
  40. 40.
    Castleden CM, George CF. The effect of ageing on the hepatic clearance of propranolol. Br J Clin Pharmacol 1979; 7(1): 49–54PubMedCrossRefGoogle Scholar
  41. 41.
    Barber HE, Hawksworth GM, Petrie JC, et al. Pharmacokinetics of atenolol and propranolol in young and elderly subjects. Br J Clin Pharmacol 1981; 11: 118P–119PGoogle Scholar
  42. 42.
    Vestal RE, Wood AJ. Influence of age and smoking on drug kinetics in man: studies using model compounds. Clin Pharmacokinet 1980; 5(4): 309–19PubMedCrossRefGoogle Scholar
  43. 43.
    Schneck DW, Luderer JR, Pritchard JF, et al. A comparison of the intrinsic clearance of propranolol in young and elderly [abstract]. Clin Pharmacol Ther 1980; 27: 284–5CrossRefGoogle Scholar
  44. 44.
    Abernethy DR, Schwartz JB, Todd EL, et al. Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients: altered electrocardiographic and hypotensive responses. Ann Intern Med 1986; 105(3): 329–36PubMedGoogle Scholar
  45. 45.
    Storstein L, Larsen A, Midtbø K, et al. Pharmacokinetics of calcium blockers in patients with renal insufficiency and in geriatric patients. Acta Med Scand Suppl 1984; 681: 25–30PubMedGoogle Scholar
  46. 46.
    Kinirons MT, Crome P. Clinical pharmacokinetic considerations in the elderly: an update. Clin Pharmacokinet 1997; 33(4): 302–12PubMedCrossRefGoogle Scholar
  47. 47.
    Turnheim K. Drug dosage in the elderly: is it rational? Drugs Aging 1998; 13(5): 357–79PubMedCrossRefGoogle Scholar
  48. 48.
    Abernethy DR. Drug therapy in the elderly. In: Atkinson AJ, Daniels CE, Dedrick RL, et al., editors. Principles of clinical pharmacology. New York: Academic Press, 2001: 307–317Google Scholar
  49. 49.
    Hammerlein A, Derendorf H, Lowenthal D. Pharmacokinetic and pharmacodynamic changes in the elderly: clinical implications. Clin Pharmacokinet 1998; 35(1): 49–64PubMedCrossRefGoogle Scholar
  50. 50.
    Hilmer SN, McLachlan AJ, LeCouteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 2007 Jun; 21(3): 217–30PubMedCrossRefGoogle Scholar
  51. 51.
    Dollery C, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone, 1999Google Scholar
  52. 52.
    Levy RH, Thummel KE, Trager WF, et al., editors. Metabolic drug interactions. Philadelphia (PA): Lippincott Williams and Wilkins, 2000Google Scholar
  53. 53.
    Sweetman SC, editor. Martindale: the complete drug reference. 34th ed. London: Pharmaceutical Press, 2005Google Scholar
  54. 54.
    Herd B, Wynne H, Wright P, et al. The effect of age on glucuronidation and sulphation of paracetamol by human liver fractions. Br J Clin Pharmacol 1991; 32(6): 768–70PubMedGoogle Scholar
  55. 55.
    Divoll M, Ameer B, Abernethy DR, et al. Age does not alter acetaminophen absorption. J Am Geriatr Soc 1982; 30(4): 240–4PubMedGoogle Scholar
  56. 56.
    Fulton B, James O, Rawlins MD. The influence of age on the pharmacokinetics of paracetamol [abstract]. Br J Clin Pharmacol 1979; 7(4): 418PPubMedCrossRefGoogle Scholar
  57. 57.
    Briant RH, Dorrington RE, Cleal J, et al. The rate of acetaminophen metabolism in the elderly and the young. J Am Geriatr Soc 1976; 24(8): 359–61Google Scholar
  58. 58.
    Triggs EJ, Nation RL, Long A, et al. Pharmacokinetics in the elderly. Eur J Clin Pharmacol 1975; 8(1): 55–62PubMedCrossRefGoogle Scholar
  59. 59.
    Divoll M, Abernethy DR, Ameer B, et al. Acetaminophen kinetics in the elderly. Clin Pharmacol Ther 1982; 31(2): 151–6PubMedCrossRefGoogle Scholar
  60. 60.
    Miners JO, Penhall R, Robson RA, et al. Comparison of paracetamol metabolism in young adult and elderly males. Eur J Clin Pharmacol 1988; 35(2): 157–60PubMedCrossRefGoogle Scholar
  61. 61.
    Bannwarth B, Pehourcq F, Lagrange F, et al. Single and multiple-dose pharmacokinetics of acetaminophen (paracetamol) in polymedicated very old patients with rheumatic pain. J Rheumatol 2001; 28(1): 182–4PubMedGoogle Scholar
  62. 62.
    Leppik IE. Metabolism of antiepileptic medication: newborn to elderly. Epilepsia 1992; 33 Suppl. 4: S32–40PubMedCrossRefGoogle Scholar
  63. 63.
    Cloyd JC, Dutta S, Cao G, et al. Valproate unbound fraction and distribution volume following rapid infusions in patients with epilepsy. Epilepsy Res 2003; 53(1–2): 19–27PubMedCrossRefGoogle Scholar
  64. 64.
    Perucca E, Grimaldi R, Gatti G, et al. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol 1984; 17(6): 665–9PubMedCrossRefGoogle Scholar
  65. 65.
    Bauer LA, Davis R, Wilensky A, et al. Valproic acid clearance: unbound fraction and diurnal variation in young and elderly adults. Clin Pharmacol Ther 1985; 37(6): 697–70PubMedCrossRefGoogle Scholar
  66. 66.
    Bryson SM, Verma N, Scott PJ, et al. Pharmacokinetics of valproic acid in young and elderly subjects. Br J Clin Pharmacol 1983; 16(1): 104–5PubMedCrossRefGoogle Scholar
  67. 67.
    Bowdle TA, Patel IH, Levy RH, et al. Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980; 28(4): 486–92PubMedCrossRefGoogle Scholar
  68. 68.
    Gidal BE, Pitterle ME, Spencer NW, et al. Relationship between valproic acid dosage, plasma concentrations and clearance in adult monotherapy patients with epilepsy. J Clin Pharmacol Ther 1995; 20(4): 215–9CrossRefGoogle Scholar
  69. 69.
    Felix S, Sproule BA, Hardy BG, et al. Dose-related pharmacokinetics and pharmacodynamics of valproate in the elderly. J Clin Psychopharmacol 2003; 23(5): 471–8PubMedCrossRefGoogle Scholar
  70. 70.
    Kodama Y, Kodama H, Kuranari M, et al. Gender- or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy. Eur J Pharm Biopharm 2001; 52(1): 57–63PubMedCrossRefGoogle Scholar
  71. 71.
    Davies NM, Anderson KE. Clinical pharmacokinetics of naproxen. Clin Pharmacokinet 1997; 32(4): 268–93PubMedCrossRefGoogle Scholar
  72. 72.
    Bowalgaha K, Elliot DJ, Mackenzie PI, et al. S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen. Br J Clin Pharmacol 2005; 60(4): 423–33PubMedCrossRefGoogle Scholar
  73. 73.
    Upton RA, Williams RL, Kelly J, et al. Naproxen pharmacokinetics in the elderly. Br J Clin Pharmacol 1984; 18(2): 207–14PubMedCrossRefGoogle Scholar
  74. 74.
    McVerry RM, Lethbridge J, Martin N, et al. Pharmacokinetics of naproxen in elderly patients. Eur J Clin Pharmacol 1986; 31(4): 463–8PubMedCrossRefGoogle Scholar
  75. 75.
    Gotzsche PC, Andreasen F, Egsmose C, et al. Steady state pharmacokinetics of naproxen in elderly rheumatics compared with young volunteers. Scand J Rheumatol 1998; 17: 11–6CrossRefGoogle Scholar
  76. 76.
    Hundal O, Rugstad H, Husby G. Naproxen free plasma concentrations and unbound fractions in patients with osteoarthritis: relation to age, sex, efficacy, and adverse events. Ther Drug Monit 1991; 13(6): 478–84PubMedCrossRefGoogle Scholar
  77. 77.
    Van den Ouweland FA, Franssen MJ, Van de Putte LB, et al. Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation. Br J Clin Pharmacol 1987; 23(2): 189–93PubMedCrossRefGoogle Scholar
  78. 78.
    Van den Ouweland FA, Gribnau FW, Van Ginneken CA, et al. Naproxen kinetics and disease activity in rheumatoid arthritis: a within-patient study. Clin Pharmacol Ther 1988; 43(1): 79–85PubMedCrossRefGoogle Scholar
  79. 79.
    Van den Ouweland FA, Jansen PA, Tan Y, et al. Pharmacokinetics of high-dosage naproxen in elderly patients. Int J Clin Pharmacol Ther Toxicol 1988; 26(3): 143–7PubMedGoogle Scholar
  80. 80.
    Anttila M, Haataja M, Kasanen A. Pharmacokinetics of naproxen in subjects with normal and impaired renal function. Eur J Clin Pharmacol 1980; 18(3): 263–8PubMedCrossRefGoogle Scholar
  81. 81.
    Cohen A, Basch C. Steady state pharmacokinetics of naproxen in young and elderly healthy volunteers. Semin Arthritis Rheum 1988; 17 (3 Suppl.2): 7–11CrossRefGoogle Scholar
  82. 82.
    Evans AM. Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs. Eur J Clin Pharmacol 1992; 42(3): 237–56PubMedCrossRefGoogle Scholar
  83. 83.
    Tan SC, Patel BK, Jackson SH, et al. Influence of age on the enantiomeric disposition of ibuprofen in healthy volunteers. Br J Clin Pharmacol 2003; 55(6): 579–87PubMedCrossRefGoogle Scholar
  84. 84.
    Rudy AC, Knight PM, Brater DC, et al. Enantioselective disposition of ibuprofen in elderly persons with and without renal impairment. J Pharmacol Exp Ther 1995; 273(1): 88–93PubMedGoogle Scholar
  85. 85.
    Albert KS, Gillespie WR, Wagner JG, et al. Effects of age on the clinical pharmacokinetics of ibuprofen. Am J Med 1984; 77(1A): 47–50PubMedCrossRefGoogle Scholar
  86. 86.
    Greenblatt DJ, Abernethy DR, Matlis R, et al. Absorption and disposition of ibuprofen in the elderly. Arthritis Rheum 1984; 27(9): 1066–9PubMedCrossRefGoogle Scholar
  87. 87.
    Karim A, Noveck R, McMahon FG, et al. Oxaprozin and piroxicam, nonsteroidal antiinflammatory drugs with long half-lives: effect of protein-binding differences on steady-state pharmacokinetics. J Clin Pharmacol 1997; 37(4): 267–78PubMedGoogle Scholar
  88. 88.
    Karim A. Inverse nonlinear pharmacokinetics of total and protein unbound drug (oxaprozin): clinical and pharmacokinetic implications. J Clin Pharmacol 1996; 36(11): 985–97PubMedCrossRefGoogle Scholar
  89. 89.
    Greenblatt DJ, Matlis R, Scavone JM, et al. Oxaprozin pharmacokinetics in the elderly. Br J Clin Pharmacol 1985; 19(3): 373–8PubMedCrossRefGoogle Scholar
  90. 90.
    Bauer LA, Blouin RA. Age and phenytoin kinetics in adult epileptics. Clin Pharmacol Ther 1982; 31(3): 301–4PubMedCrossRefGoogle Scholar
  91. 91.
    Bachmann KA, Belloto Jr RJ. Differential kinetics of phenytoin in elderly patients. Drugs Aging 1999; 15(3): 235–50PubMedCrossRefGoogle Scholar
  92. 92.
    Crowley JJ, Cusack BJ, Jue SG, et al. Aging and drug interactions: II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men. J Pharmacol Exp Ther 1988; 245(2): 513–23PubMedGoogle Scholar
  93. 93.
    Deleu D, Aarons L, Ahmed IA. Estimation of population pharmacokinetic parameters of free phenytoin in adult epileptic patients. Arch Med Res 2005; 36(1): 49–53PubMedCrossRefGoogle Scholar
  94. 94.
    Hayes MJ, Langman MJ, Short AH. Changes in drug metabolism with increasing age: 2. Phenytoin clearance and protein binding. Br J Clin Pharmacol 1975; 2(1): 73–9PubMedGoogle Scholar
  95. 95.
    Valodia P, Seymour MA, Miller R, et al. Factors influencing the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa. Ther Drug Monit 1999; 21(1): 57–62PubMedCrossRefGoogle Scholar
  96. 96.
    Frame B, Beal SL. Non-steady state population kinetics of intravenous phenytoin. Ther Drug Monit 1998; 20(4): 408–16PubMedCrossRefGoogle Scholar
  97. 97.
    Battino D, Croci D, Mamoli D, et al. Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data. Epilepsy Res 2004; 59(2–3): 155–65PubMedCrossRefGoogle Scholar
  98. 98.
    Lambie DC, Caird FI. Phenytoin dosage in the elderly. Age Ageing 1977; 6(3): 133–7PubMedCrossRefGoogle Scholar
  99. 99.
    Hudson S, Farquhar DL, Thompson D, et al. Phenytoin dosage individualization: five methods compared in the elderly. J Clin Pharmacol Ther 1990; 15(1): 25–34CrossRefGoogle Scholar
  100. 100.
    Hooper WD, Bochner F, Eadie MJ, et al. Plasma protein binding of diphenylhydantoin: effects of sex hormones, renal and hepatic diseases. Clin Pharmacol Ther 1974; 15(3): 276–82PubMedGoogle Scholar
  101. 101.
    Patterson M, Heazelwood R, Smithurst B, et al. Plasma protein binding of phenytoin in the aged: in vivo studies. Br J Clin Pharmacol 1982; 13(3): 423–5PubMedCrossRefGoogle Scholar
  102. 102.
    Iwamoto T, Kagawa Y, Naito Y, et al. Clinical evaluation of plasma free phenytoin measurement and factors influencing its protein binding. Biopharm Drug Dispos 2006; 27(2): 77–84PubMedCrossRefGoogle Scholar
  103. 103.
    Verbeeck RK, Cardinal JA, Wallace SM. Effect of age and sex on the plasma binding of acidic and basic drugs. Eur J Clin Pharmacol 1984; 27(1): 91–7PubMedGoogle Scholar
  104. 104.
    Peterson GM, McLean S, Aldous S, et al. Plasma protein binding of phenytoin in 100 epileptic patients. Br J Clin Pharmacol 1982; 14(2): 298–300PubMedCrossRefGoogle Scholar
  105. 105.
    Banh HL, Burton ME, Sperling MR. Interpatient and intrapatient variability in phenytoin protein binding. Ther Drug Monit 2002; 24(3): 379–85PubMedCrossRefGoogle Scholar
  106. 106.
    Birnbaum A, Hardie NA, Leppik IE, et al. Variability of total phenytoin serum concentrations within elderly nursing home residents. Neurology 2003; 60(4): 555–9PubMedCrossRefGoogle Scholar
  107. 107.
    Mooradian AD, Hernandez L, Tamai IC, et al. Variability of serum phenytoin concentrations in nursing home patients. Arch Intern Med 1989; 149(4): 890–2PubMedCrossRefGoogle Scholar
  108. 108.
    Sherwin AL, Loynd JS, Bock GW, et al. Effects of age, sex, obesity, and pregnancy on plasma diphenylhydantoin levels. Epilepsia 1974; 15(4): 507–21PubMedCrossRefGoogle Scholar
  109. 109.
    Houghton GW, Richens A, Leighton M. Effect of age, height, weight and sex on serum phenytoin concentration in epileptic patients. Br J Clin Pharmacol 1975; 2(3): 251–6PubMedCrossRefGoogle Scholar
  110. 110.
    Grasela TH, Sheiner LB, Rambeck B, et al. Steady-state pharmacokinetics of phenytoin from routinely collected patient data. Clin Pharmacokinet 1983; 8(4): 355–64PubMedCrossRefGoogle Scholar
  111. 111.
    Chan E, Ti TY, Lee HS. Population pharmacokinetics of phenytoin in Singapore Chinese. Eur J Clin Pharmacol 1990; 39(2): 177–81PubMedCrossRefGoogle Scholar
  112. 112.
    Ismail R, Rahman AF, Chand P. Pharmacokinetics of phenytoin in routine clinic patients in Malaysia. J Clin Pharmacol Ther 1994; 19(4): 245–8CrossRefGoogle Scholar
  113. 113.
    Driscoll DDF, McMahon M, Blackburn GL, et al. Phenytoin toxicity in a critically ill, hypoalbuminemic patient with normal serum drug concentrations. Crit Care Med 1988; 16(12): 1248–9PubMedCrossRefGoogle Scholar
  114. 114.
    Blocka KL, Richardson CJ, Wallace SM, et al. The effect of age on piroxicam disposition in rheumatoid arthritis. J Rheumatol 1988; 15(5): 757–63PubMedGoogle Scholar
  115. 115.
    Richardson CJ, Blocka KL, Ross SG, et al. Effects of age and sex on piroxicam disposition. Clin Pharmacol Ther 1985; 37(1): 13–8PubMedCrossRefGoogle Scholar
  116. 116.
    Rudy AC, Figueroa NL, Hall SD, et al. The pharmacokinetics of piroxicam in elderly persons with and without renal impairment. Br J Clin Pharmacol 1994; 37(1): 1–5PubMedCrossRefGoogle Scholar
  117. 117.
    Woolf AD, Rogers HJ, Bradbrook ID, et al. Pharmacokinetic observations on piroxicam in young adult, middle-aged and elderly patients. Br J Clin Pharmacol 1983; 16(4): 433–7PubMedCrossRefGoogle Scholar
  118. 118.
    Herman RJ, Wilkinson GR. Disposition of diazepam in young and elderly subjects after acute and chronic dosing. Br J Clin Pharmacol 1996; 42(2): 147–55PubMedCrossRefGoogle Scholar
  119. 119.
    Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975; 55(2): 347–59PubMedCrossRefGoogle Scholar
  120. 120.
    Greenblatt DJ, Allen MD, Harmatz JS, et al. Diazepam disposition determinants. Clin Pharmacol Ther 1980; 27(3): 301–12PubMedCrossRefGoogle Scholar
  121. 121.
    Macklon AF, Barton M, James O, et al. The effect of age on the pharmacokinetics of diazepam. Clin Sci (Colch) 1980; 59(6): 479–83Google Scholar
  122. 122.
    Ochs HR, Greenblatt DJ, Divoll M, et al. Diazepam kinetics in relation to age and sex. Pharmacology 1981; 23(1): 24–30PubMedCrossRefGoogle Scholar
  123. 123.
    Abel JG, Sellers EM, Naranjo CA, et al. Inter- and intrasubject variation in diazepam free fraction. Clin Pharmacol Ther 1979; 26(2): 247–55PubMedGoogle Scholar
  124. 124.
    Naranjo CA, Sellers EM, Giles HG, et al. Diurnal variations in plasma diazepam concentrations associated with reciprocal changes in free fraction. Br J Clin Pharmacol 1980; 9(3): 265–72PubMedCrossRefGoogle Scholar
  125. 125.
    Naranjo CA, Sellers EM, Khouw V. Fatty acids modulation of meal-induced variations in diazepam free fraction. Br J Clin Pharmacol 1980; 10(3): 308–10PubMedCrossRefGoogle Scholar
  126. 126.
    Greenblatt DJ, Allen MD, Locniskar A, et al. Lorazepam kinetics in the elderly. Clin Pharmacol Ther 1979; 26(1): 103–23PubMedGoogle Scholar
  127. 127.
    Divoll M, Greenblatt DJ. Effect of age and sex on lorazepam protein binding. J Pharm Pharmacol 1982; 34(2): 122–3PubMedCrossRefGoogle Scholar
  128. 128.
    Kraus JW, Desmond PV, Marshall JP, et al. Effects of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther 1978; 24(4): 411–9PubMedGoogle Scholar
  129. 129.
    Aaltonen L, Kanto L, Arola J, et al. Effect of age and cardiopulmonary bypass on the pharmacokinetics of lorazepam. Acta Pharmacol Toxicol 1982; 51(2): 126–31CrossRefGoogle Scholar
  130. 130.
    Barr J, Zomorodi K, Bertaccini EJ, et al. A double-blind, randomized comparison of IV lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model. Anesthesiology 2001; 95(2): 286–98PubMedCrossRefGoogle Scholar
  131. 131.
    Swart EL, Zuideveld KP, de Jongh J, et al. Comparative population pharmacokinetics of lorazepam and midazolam during long-term continuous infusion in critically ill patients. Br J Clin Pharmacol 2004; 57(2): 135–45PubMedCrossRefGoogle Scholar
  132. 132.
    Divoll M, Greenblatt DJ, Harmatz JS, et al. Effect of age and gender on disposition of temazepam. J Pharm Sci 1981; 70(10): 1104–7PubMedCrossRefGoogle Scholar
  133. 133.
    Ghabrial H, Desmond PV, Watson KJ, et al. The effects of age and chronic liver disease on the elimination of temazepam. Eur J Clin Pharmacol 1986; 30(1): 93–7PubMedCrossRefGoogle Scholar
  134. 134.
    Smith RB, Divoll M, Gillespie WR, et al. Effect of subject age and gender on the pharmacokinetics of oral triazolam and temazepam. J Clin Psychopharmacol 1983; 3(3): 172–6PubMedCrossRefGoogle Scholar
  135. 135.
    Yacobi A, Udall JA, Levy G. Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect. Clin Pharmacol Ther 1976; 19 (5 Pt1): 552–8Google Scholar
  136. 136.
    Yacobi A, Udall JA, Levy G. Intrasubject variation of warfarin binding to protein in serum of patients with cardiovascular disease. Clin Pharmacol Ther 1976; 20(3): 300–3PubMedGoogle Scholar
  137. 137.
    Herman D, Locatelli I, Grabnar I, et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics J 2005; 5(3): 193–202PubMedCrossRefGoogle Scholar
  138. 138.
    Routledge PA, Chapman PH, Davies DM, et al. Pharmacokinetics and pharmacodynamics of warfarin at steady state. Br J Clin Pharmacol 1979; 8(3): 243–7PubMedCrossRefGoogle Scholar
  139. 139.
    Gurwitz JH, Avorn J, Ross-Degnan D, et al. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 1992; 116(11): 901–4PubMedGoogle Scholar
  140. 140.
    Redwood M, Taylor C, Bain BJ, et al. The association of age with dosage requirement for warfarin. Age Ageing 1991; 20(3): 217–20PubMedCrossRefGoogle Scholar
  141. 141.
    Wynne HA, Kamali F, Edwards C, et al. Effect of aging upon warfarin requirements: a longitudinal study. Age Ageing 1996; 25(6): 429–31PubMedCrossRefGoogle Scholar
  142. 142.
    Shepherd AM, Hewick DS, Moreland TA, et al. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 4(3): 315–20PubMedCrossRefGoogle Scholar
  143. 143.
    Wynne H, Cope L, Kelly P, et al. The influence of age, liver size and enantiomer concentrations on warfarin requirements. Br J Clin Pharmacol 1995; 40(3): 203–7PubMedGoogle Scholar
  144. 144.
    Hotraphinyo K, Triggs EJ, Maybloom B, et al. Warfarin sodium: steady-state plasma levels and patient age. Clin Exp Pharmacol Physiol 1978; 5(2): 143–9PubMedCrossRefGoogle Scholar
  145. 145.
    Bradbury H, Burns E, Stanners A, et al. The clearance of warfarin and its enantiomers in the elderly. Br J Clin Pharmacol 1992; 34(2): 154P–5PGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyChristchurch HospitalChristchurchNew Zealand
  2. 2.Department of MedicineUniversity of OtagoChristchurchNew Zealand

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