The Aging Liver

Drug Clearance and an Oxygen Diffusion Barrier Hypothesis

Abstract

A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations.

Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the ‘oxygen diffusion barrier’ hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion.

Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Offerhaus L. Drags for the elderly. 2nd ed. Copenhagen: WHO Regional Publications, 1997.

    Google Scholar 

  2. 2.

    Le Couteur DG, Johnson AG. Drags and the elderly: prescription idiosyncrasies. Mod Med. 1997; 40: 30–7.

    Google Scholar 

  3. 3.

    Hurwitz N. Predisposing factors in adverse reactions to drugs. BMJ. 1969; I: 536–9.

    Article  Google Scholar 

  4. 4.

    Lumley CE, Walker SR, Hall GC, et al. The under-reporting of adverse drug reactions seen in general practice. Pharm Med. 1986; 1: 205–12.

    Google Scholar 

  5. 5.

    Hutchinson TA, Flegel KM, Kramer MS, et al. Frequency, severity and risk factors for adverse drag reactions in adult outpatients. J Chron Dis. 1986; 39: 533–42.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Monette J, Gurwitz JH, Avom J. Epidemiology of adverse drag events in the nursing home setting. Drugs Aging. 1995; 7: 203–11.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Gurwitz JH, Avorn J. The ambiguous relation between aging and adverse drag reactions. Ann Intern Med. 1991; 114: 956–67.

    PubMed  CAS  Google Scholar 

  8. 8.

    Popper H. Aging and the liver. Prog Liver Dis. 1986; VIII: 659–83.

    Google Scholar 

  9. 9.

    Vestal RE. Aging and determinants of hepatic drug clearance. Hepatology. 1989; 9: 331–4.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Kinirons MT, Crome P. Clinical pharmacokinetic considerations in the elderly: an update. Clin Pharmacokinet. 1997; 33: 302–12.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Schmucker DL. Aging and drug disposition: an update. Pharmacol Rev. 1979; 30: 133–48.

    Google Scholar 

  12. 12.

    James OFW. Drugs and the ageing liver. J Hepatol. 1985; 1: 431–5.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Woodhouse K. Drags and the liver. III: aging of the liver and the metabolism of drags. Biopharm Drug Dispos. 1992; 13: 311–20.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Woodhouse KW, Mutch E, Williams FM. The effect of age on pathways of drug metabolism in human liver. Age Ageing. 1984; 13: 328–34.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Wynne HA, James OFW. The aging liver. Age Ageing. 1990; 19: 1–3.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Wilkinson GR. The effects of diet, aging and disease-states on presystemic elimination and oral drug bioavailability in humans. Adv Drug Deliv Rev. 1997; 27: 129–59.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Boyd E. Normal variability in weight of the adult human liver and spleen. Arch Pathol. 1933; 16: 350–72.

    Google Scholar 

  18. 18.

    Calloway NO, Foley CF, Lagerbloom P. Uncertainties in geriatric data. II: organ size. J Am Geriatr Soc. 1965; 13: 20–8.

    PubMed  CAS  Google Scholar 

  19. 19.

    Tauchi H, Sato T. Hepatic cells of the aged. In: Kitani K, editor. Liver and aging. Amsterdam: Elsevier North Holland, 1978: 3–20.

    Google Scholar 

  20. 20.

    Bach B, Hansen JM, Kampmann JP, et al. Disposition of antipyrine and phenytoin correlated with age and liver volume in man. Clin Pharmacokinet. 1981; 6: 389–96.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Schnegg M, Lauterburg BH. Quantitative liver function in the elderly assessed by galactose elimination capacity, aminopyrine demethylation and caffeine clearance. J Hepatol. 1986; 3: 164–71.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Wynne HA, Cope LH, James OFW, et al. The effect of age and frailty upon acetanilide clearance in man. Age Ageing. 1989; 18: 415–8.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Wynne HA, Cope LH, Mutch E, et al. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989; 9: 297–301.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Varga F, Fischer E. Age dependent changes in blood supply of the liver and in the biliary excretion of eosine in rats. In: Kitani K, editor. Liver and aging. Amsterdam: Elsevier North Holland, 1978: 327–42.

    Google Scholar 

  25. 25.

    Wiener E, Rabinovici N. Liver haemodynamics and age. Proc Soc Exp Biol Med. 1961; 108: 752–4.

    PubMed  CAS  Google Scholar 

  26. 26.

    Montgomery PR, Sitar DS. Hepatic uptake of indocyanine green and perfusion rate in rats: effect of age and albumin concentration. Can J Physiol Pharmacol. 1988; 66: 592–5.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Le Couteur DG, Rivory LP, Yi C, et al. Aging, acute oxidative injury and hepatocellular glucose transport in the rat. Int Hepatol Commun. 1995; 3: 244–53.

    Article  Google Scholar 

  28. 28.

    Martin G, Sewell B, Yeomans ND, et al. Ageing has no effect on the volume density of hepatocytes, reticulo-endothelial cells or the extracellular space in livers of female Sprague-Dawley rats. Clin Exp Pharmacol Physiol. 1992; 19: 537–9.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Schmucker DL. A quantitative morphological evaluation of hepatocytes in young mature and senescent fischer 344 male rats. In: Kitani K, editor. Liver and aging. Amsterdam: Elsevier North Holland, 1978: 21–38.

    Google Scholar 

  30. 30.

    Pieri C, Zs-Nagy I, Mazzufferri G, et al. The aging of rat liver as revealed by electron microscopic morphometry. I: basic parameters. Exp Gerontol. 1975; 10: 291–304.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Van Bezooijen CFA. Influence of age-related changes in rodent liver morphology and physiology on drug metabolism: a review. Mech Ageing Devel. 1984; 25: 1–22.

    Article  Google Scholar 

  32. 32.

    Sastre J, Pallardo FV, Pla R, et al. Aging of the liver: age-associated mitochondrial damage in intact hepatocytes. Hepatology. 1996; 24: 1199–205.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Sherlock S, Beam AG, Billing BH, et al. Splanchnic blood flow in man by the bromosulfthalein method: the relation of peripheral plasma bromosulfthalein level to calculated flow. J Lab Clin Med. 1950; 35: 923–32.

    PubMed  CAS  Google Scholar 

  34. 34.

    Zoli M, Iervese T, Abbati S, et al. Portal blood flow and velocity in aging man. Gerontology. 1989; 35: 61–5.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Wynne HA, Goudevenos J, Rawlins MD, et al. Hepatic drug clearance: the effect of age using indocyanine green as a model compound. Br J Clin Pharmacol. 1990; 30: 634–7.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Le Couteur DG, Rivory LP, Roberts MS, et al. Aging and the response of the isolated perfused rat liver to vasoactive drugs. Biochem Pharmacol. 1992; 43: 913–5.

    PubMed  Article  Google Scholar 

  37. 37.

    Lautt WW, Greenway CV. Conceptual review of the hepatic vascular bed. Hepatology. 1987; 7: 952–63.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Handler JA, Genell CA, Goldstein RS. Hepatobiliary function in senescent male Sprague-Dawley rats. Hepatology. 1994; 19: 1496–503.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Finch CE. Enzyme activities, gene function and aging in mammals. Exp Gerontol. 1972; 7: 53–67.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Ward W, Richardson A. Effect of age on liver protein synthesis and degradation. Hepatology. 1991; 5: 935–49.

    Article  Google Scholar 

  41. 41.

    Greenblatt DJ. Reduced serum albumin concentration in the elderly: a report from the Boston Collaborative Drug Surveillance Program. J Am Geriatr Soc. 1979; 27: 20–2.

    PubMed  CAS  Google Scholar 

  42. 42.

    Campion EW, deLabry LO, Glynn RJ. The effect of age on serum albumin in healthy males: report from the Normative Aging Study. J Gerontol. 1988; 43: M18–20.

    PubMed  CAS  Google Scholar 

  43. 43.

    Chen JC, Ove P, Lansing AI. In vitro synthesis of microsomal protein and albumin in young and old rats. Biochim Biophys Acta. 1977; 312: 598–607.

    Google Scholar 

  44. 44.

    Santa Maria C, Ayala A, Revilla E. Changes in Superoxide dismutase activity in liver and lung of old rats. Free Radical Res. 1996; 25: 401–5.

    Article  CAS  Google Scholar 

  45. 45.

    Stio M, Iantomasi T, Favilli F, et al. Glutathione metabolism in heart and liver of the aging rat. Biochem Cell Biol. 1994; 72: 58–61.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Rikans LE. Influence of aging on the susceptibility of rats to hepatoxic injury. Toxicol Appl Pharmacol. 1984; 73: 243–9.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Rikans LE. Age-related differences in the susceptibility to druginduced hepatotoxicity. In: Kitani K, editor. Liver and aging. Amsterdam: Excerpta Medica, 1991: 59–71.

    Google Scholar 

  48. 48.

    Le Couteur DG, Rivory LP, Pond SM. The effects of aging and nutritional state on hypoxia-reoxygenation injury in the perfused rat liver. Transplantation. 1994; 58: 531–6.

    PubMed  Article  Google Scholar 

  49. 49.

    Mooney H, Roberts R, Cooksley WGE, et al. Alterations in liver with aging. Clin Gastroenterol. 1985; 14: 757–71.

    PubMed  CAS  Google Scholar 

  50. 50.

    Kampmann JP, Sinding J, Moller-Jorgensen I. Effect of age on liver function. Geriatrics. 1975; 30: 91–5.

    PubMed  CAS  Google Scholar 

  51. 51.

    Gibson PR, Dudley FL. Ischemic hepatitis: clinical features, diagnosis, and prognosis. Aust NZ J Med. 1984; 14: 822–5.

    Article  CAS  Google Scholar 

  52. 52.

    Kato R, Vassanelli P, Frontino G. Variation in the activity of liver microsomal drug metabolising enzymes in rats in relation to age. Biochem Pharmacol. 1964; 12: 1037–51.

    Article  Google Scholar 

  53. 53.

    Iwamoto K, Watanabe J, Araki K, et al. Effect of age on the hepatic clearance of propranolol in rats. J Pharm Pharmacol. 1985; 37: 466–70.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Schmucker DL, Woodhouse KW, Wang RK, et al. Effects of age and gender on in vitro properties of human liver microsomal monooxygenases. Clin Pharmacol Ther. 1990; 48: 365–74.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994; 270: 414–23.

    PubMed  CAS  Google Scholar 

  56. 56.

    Brodie MJ, Boobis AR, Bulpitt CJ, et al. Influence of liver disease and environmental factors on hepatic monooxygenase activity in vitro. Eur J Clin Pharmacol. 1981; 20: 39–46.

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Hunt CM, Strater S, Stave GM. Effect of normal aging on the activity of human hepatic cytochrome P450IIE1. Biochem Pharmacol. 1990; 40: 1666–9.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Herd B, Wynne HA, Wright P, et al. The effect of age on glucuronidation and sulphation of paracetamol by human liver fractions. Br J Clin Pharmacol. 1991; 32: 768–70.

    PubMed  CAS  Google Scholar 

  59. 59.

    Durnas C, Loi CM, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet. 1990; 19: 359–89.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Vestal RE, Wood AJJ, Branch RA, et al. Studies of drug disposition in the elderly using model compounds. In: Kitani K, editor. Liver and aging. Amsterdam: Elsevier North Holland, 1978: 343–57.

    Google Scholar 

  61. 61.

    Rowland M, Tozer TN. Clinical Pharmacokinetics: concepts and applications. Philadelphia: Lea & Febiger, 1989.

    Google Scholar 

  62. 62.

    Angus PW, Mihaly GW, Morgan DJ, et al. Oxygen dependence of omeprazole clearance and suphone and suphide metabolite formation in the isolated perfused rat liver. J Pharmacol Ther. 1989; 250: 1043–7.

    CAS  Google Scholar 

  63. 63.

    Angus PW, Mihaly GW, Morgan DJ, et al. Oxygen dependence of salbutamol elimination by the isolated perfused rat liver. Biochem Pharmacol. 1989; 38: 1443–9.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Angus PW, Morgan DJ, Smallwood RA. Hypoxia and hepatic drug metabolism: clinical implications. Aliment Pharmacol Ther. 1990; 4: 213–25.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet. 1991; 21: 42–69.

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet. 1995; 29: 1–22.

    Article  Google Scholar 

  67. 67.

    Owens N, Fretwell M, Willey C, et al. Distinguishing between the fit and frail elderly, and optimising pharmacotherapy. Drugs Aging. 1994; 4: 47–55.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Iber FL, Murphy PA, Connor ES. Age-related changes in the gastrointestinal system: effects on drug therapy. Drugs Aging. 1994; 5: 34–48.

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Kitani K. Hepatic drug metabolism in the elderly. Hepatology. 1986; 6: 316–9.

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Sotaneimi EA, Arranto AT, Pelkonen O, et al. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathological conditions. Clin Pharmacol Ther. 1997; 61: 331–9.

    Article  Google Scholar 

  71. 71.

    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: 91–7.

    PubMed  CAS  Google Scholar 

  72. 72.

    Patterson M, Heazelwood R, Shithurst B, et al. Plasma protein binding of phenytoin in the aged: in vivo studies. Br J Clin Pharmacol. 1982; 13: 423–5.

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Davis D, Grossman SH, Kitchell BB, et al. The effects of aging and smoking on the plasma protein binding of lignocaine and diazepam. Br J Clin Pharmacol. 1985; 19: 261–5.

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Boudinot SG, Funderburg ED, Boudinot FD. Effects of age on the pharmacokinetics of piroxicam in rats. J Pharm Sci. 1993; 82: 254–7.

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Andros E, Detmar-Hanna D, Suteparuk S, et al. The effect of aging on the pharmacokinetics and pharmacodynamics of prazosin. Eur J Clin Pharmacol. 1996; 50: 41–6.

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Shepherd AM, Hewick DS, Moreland TA, et al. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977; 4: 315–20.

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Schwartz JB, Capili H, Daugherty J. Aging of women alters S-verapamil pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 1994; 55: 509–17.

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Bernus I, Dickinson RG, Hooper WD, et al. Anticonvulsant therapy in aged patients: clinical pharmacokinetic considerations. Drugs Aging. 1997; 10: 278–89.

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Wallace SM, Verbeeck RK. Plasma protein binding of drugs in the elderly. Clin Pharmacokinet. 1987; 12: 41–72.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Branch RA. Drugs as indicators of hepatic function. Hepatology. 1982; 2: 97–105.

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Branch RA, Shand DG. Propranolol disposition in chronic liver disease: a physiological approach. Clin Pharmacokinet. 1976; 1: 264–79.

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Greenblatt DJ, Divoll M, Abernethy DR, et al. Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity. Br J Clin Pharmacol. 1982; 15: 303–9.

    Article  Google Scholar 

  83. 83.

    Varin F, Huet P-M. Hepatic microcirculation in the perfused cirrhotic rat liver. J Clin Invest. 1985; 76: 1904–12.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Hickey PL, McLean AJ, Angus PW, et al. Increased sensitivity of propranolol clearance to reduced oxygen delivery in the isolated perfused cirrhotic rat liver. Gastroenterology. 1996; 111: 1039–48.

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Kassissia I, Rose CP, Goresky CA, et al. Flow-limited tracer oxygen distribution in the isolated perfused rat liver: effects of temperature and hematocrit. Hepatology. 1992; 16: 763–75.

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Hickey PL, Angus PW, McLean AT, et al. Oxygen supplementation restores theophylline clearance to normal in cirrhotic rats. Gastroenterology. 1995; 108: 1504–9.

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Rose CP, Goresky CA. Limitation of tracer oxygen uptake in the canine coronary circulation. Circ Res. 1985; 56: 57–71.

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Blanchard J, Sawers SJA. Comparative pharmacokinetics of caffeine in young and elderly men. J Pharm Biopharm. 1983; 11: 109–29.

    CAS  Google Scholar 

  89. 89.

    Pirke KM, Sintermann R, Vogt HJ. Testosterone and testosterone precursors in the spermatic vein and in the testicular tissue of old men: reduced oxygen suppy may explain the relative increase of testicular progesterone and 17a-hydroxyprogesterone content and production in old age. Gerontology. 1980; 26: 221–30.

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Le Couteur D. The physiology of the aging liver. Brisbane: The University of Queensland, 1994.

    Google Scholar 

  91. 91.

    Vaz M, Rajkumar C, Wong J, et al. Oxygen consumption in the heart, hepatomesenteric bed and brain in young and elderly human subjects and accompanying sympathetic nervous activity. Metabolism. 1996; 45: 1487–92.

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    De Leeuw AM, Brouwer A, Knook DL. Sinusoidal endothelial cells of the liver: fine structure and function in relation to age. J Electron Microsc Tech. 1990; 14: 218–36.

    PubMed  Article  Google Scholar 

  93. 93.

    Guenard H, Marthan R. Pulmonary gas exchange in elderly subjects. Eur Resp J. 1996; 9: 2573–7.

    Article  CAS  Google Scholar 

  94. 94.

    Le Couteur DG, Rivory LP, Pond SM. Hepatic intracellular pH during the prereplicative period following partial hepatectomy. Am J Physiol. 1993; 264: G767–73.

    PubMed  Google Scholar 

  95. 95.

    McLean AJ, Le Couteur DG. The effect of age on the hepatocyte uptake of solutes [abstract]. Clin Pharmacol Ther 1998. In press.

  96. 96.

    Zs-Nagy I. The role of membrane structure and function in cellular aging: a review. Mech Ageing Devel. 1979; 9: 237–46.

    Article  CAS  Google Scholar 

  97. 97.

    Nokubo M. Physical-chemical and biochemical differences in liver plasma membranes in aging F-344 rats. J Gerontol. 1985; 40: 409–14.

    PubMed  CAS  Google Scholar 

  98. 98.

    Zs-Nagy I, Geynes M, Lustik G, et al. Age-dependent decrease of cell membrane permeability of rat hepatocytes as revealed by in vivo Rb+-uptake and release. In: Kitani K, editor. Liver and aging. Amsterdam: Elsevier Biomedical Press, 1982: 215–28.

    Google Scholar 

  99. 99.

    Kitani K, Zsolnai-Nagy I, Kanai S, et al. Correlation between the biliary excretion of ouabain and the lateral mobility of hepatocyte plasma membrane proteins in the rat: the effects of age and spironolactone pretreatment. Hepatology. 1988; 8: 125–31.

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Gentile S, Persico M, Orlando C, et al. Age-associated decline of hepatic handling of cholephilic anions in humans is reverted by S-adenosylmethionine (SAMe). Scand J Clin Lab Invest. 1990; 50: 565–71.

    PubMed  Article  CAS  Google Scholar 

  101. 101.

    Hegner D. Age-dependence of molecular and functional changes in biological membrane properties. Mech Ageing Devel. 1980; 14: 101–18.

    Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Professor Allan J. McLean.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Le Couteur, D.G., McLean, A.J. The Aging Liver. Clin Pharmacokinet 34, 359–373 (1998). https://doi.org/10.2165/00003088-199834050-00003

Download citation

Keywords

  • Adis International Limited
  • Antipyrine
  • Hepatic Blood Flow
  • Drug Clearance
  • Intrinsic Clearance