Alterations in drug disposition in older adults

Expert Opinion on Drug Metabolism and Toxicology

Volumn 11, Issue 4, 2015, Pages 491-508

  Reeve, Emily ^a   Wiese, Michael D ^b   Mangoni, Arduino A ^c  

^a UNIVERSITY OF SYDNEY   (Australia)

^b UNIVERSITY OF SOUTH AUSTRALIA   (Australia)

^c FLINDERS MEDICAL CENTRE   (Australia)

Author keywords

Absorption; Aging; Distribution; Elimination; Metabolism; Pharmacokinetics

Indexed keywords

ADULT; AGING; BODY COMPOSITION; CLINICAL PRACTICE; DRUG ABSORPTION; DRUG DISPOSITION; DRUG ELIMINATION; DRUG METABOLISM; DRUG PENETRATION; FIRST PASS EFFECT; HUMAN; KIDNEY DISEASE; KIDNEY FUNCTION; LIVER BLOOD FLOW; LIVER CELL; NASOGASTRIC TUBE; PLASMA PROTEIN BINDING; REVIEW; STOMACH PH; AGE; AGED; ANIMAL; METABOLISM; PHARMACOKINETICS; PHYSIOLOGY; VERY ELDERLY;

DRUG;

AGE FACTORS; AGED; AGED, 80 AND OVER; AGING; ANIMALS; HUMANS; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS;

EID: 84924794952     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2015.1004310     Document Type: Review

References (181)

1. United Nations Department of Economic and Social Affairs Population Division. World population ageing 2013. United Nations publication, New York: 2013
2. Fedarko NS. The biology of aging and frailty. Clin Geriatr Med 2011;27:27-37
3. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol 1995;27:647-53
4. Higami Y, Shimokawa I. Apoptosis in the aging process. Cell Tissue Res 2000;301:125-32
5. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004;56:163-84
6. Sera LC, McPherson ML. Pharmacokinetics and pharmacodynamic changes associated with aging and implications for drug therapy. Clin Geriatr Med 2012;28:273-86
7. Kirkwood TBL, Austad SN. Why do we age?. Nature 2000;408:233-8
8. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol 2004;57:6-14
9. Amella EJ. Presentation of illness in older adults. If you think you know what you're looking for, think again. AORN J 2006;83:372-89
10. Schmader KE, Baron R, Haanpaa ML, et al. Treatment considerations for elderly and frail patients with neuropathic pain. Mayo Clin Proc 2010;85:S26-32
11. Schmucker D. Liver function and phase I drug metabolism in the elderly. Drugs Aging 2001;18:837-51
12. Hilmer SN. ADME-Tox issues for the elderly. Expert Opin Drug Metab Toxicol 2008;4:1321-31
13. Nelson EA, Dannefer D. Aged heterogeneity: fact or fiction?. The fate of diversity in gerontological research. Gerontologist 1992;32:17-23
14. Deneer VHM, Van Hemel NM. Is antiarrhythmic treatment in the elderly different?: a review of the specific changes. Drugs Aging 2011;28:617-33
15. Shi S, Morike K, Klotz U. The clinical implications of ageing for rational drug therapy. Eur J Clin Pharmacol 2008;64:183-99
16. Lehnert T, Heider D, Leicht H, et al. Review: health care utilization and costs of elderly persons with multiple chronic conditions. Med Care Res Rev 2011;68:387-420
17. Australian Institute of Health and Welfare. Older Australia at a glance. AIHW; Canberra: 2007
18. Prescriptions dispensed in the community. Statistics for 1996 to 2006. The Information Centre (Health Care), England: 2007
19. Mangoni AA. Predicting and detecting adverse drug reactions in old age: challenges and opportunities. Expert Opin Drug Metab Toxicol 2012;8:527-30
20. Ginsberg G, Hattis D, Russ A, Sonawane B. Pharmacokinetic and pharmacodynamic factors that can affect sensitivity to neurotoxic sequelae in elderly individuals. Environ Health Perspect 2005;113:1243-9
21. Hochhaus G, Barrett JS, Derendorf H. Evolution of pharmacokinetics and pharmacokinetic/dynamic correlations during the 20th century. J Clin Pharmacol 2000;40:908-17
22. Mangoni AA. The impact of advancing age on P-glycoprotein expression and activity: current knowledge and future directions. Expert Opin Drug Metab Toxicol 2007;3:315-20
23. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009;41:67-76
24. Feldman M. The mature stomach: still pumping out acid?. JAMA 1997;278:681-2
25. Blechman MB, Gelb AM. Aging and gastrointestinal physiology. Clin Geriatr Med 1999;15:429-38
26. Hurwitz A, Brady DA, Schaal S, et al. Gastric acidity in older adults. JAMA 1997;278:659-62
27. Nakamura K, Ogoshi K, Makuuchi H. Influence of aging, gastric mucosal atrophy and dietary habits on gastric secretion. Hepatogastroenterology 2006;53:624-8
28. Geller AM, Zenick H. Aging and the environment: a research framework. Environ Health Perspect 2005;113:1257-62
29. Schmucker D. Aging and drug disposition: an update. Pharmacol Rev 1985;37:133-48
30. Hurwitz A, Ruhl CE, Kimler BF, et al. Gastric function in the elderly: effects on absorption of ketoconazole. J Clin Pharmacol 2003;43:996-1002
31. Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008;47:47-59
32. Gidal BE. Drug absorption in the elderly: biopharmaceutical considerations for the antiepileptic drugs. Epilepsy Res 2006;68(Suppl 1):S65-9
33. Abruzzo CW, Macasieb T, Weinfeld R, et al. Changes in the oral absorption characteristics in man of dipotassium clorazepate at normal and elevated gastric pH. J Pharmacokinet Biopharm 1977;5:377-90
34. O'Mahony D, O'Leary P, Quigley EM. Aging and intestinal motility. Drugs Aging 2002;19:515-27
35. Drozdowski L, Thomson AB. Aging and the intestine. World J Gastroenterol 2006;12:7578-84
36. Wilding I, Davis S, Hardy J, et al. Relationship between systemic drug absorption and gastrointestinal transit after the simultaneous oral administration of carbamazepine as a controlled-release system and as a suspension of 15Nlabelled drug to healthy volunteers. Br J Clin Pharmacol 1991;32:573-9
37. Yeh K, August T, Bush D, et al. Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 1989;39:25-38
38. Kaiko RF, Benzinger DP, Fitzmartin RD, et al. Pharmacoltinetic-pharmacodynamic relationships of controlled-release oxycodone. Clin Pharmacol Ther 1996;59:52-61
39. Orr WC, Chen CL. Aging and neural control of the GI tract: IV. Clinical and physiological aspects of gastrointestinal motility and aging. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226-31
40. Gainsborough N, Maskrey VL, Nelson ML, et al. The association of age with gastric emptying. Age Ageing 1993;22:37-40
41. Valentini L, Ramminger S, Haas V, et al. Small intestinal permeability in older adults. Physiol Rep 2014;2:e00281
42. Turnheim K. Drug therapy in the elderly. Exp Gerontol 2004;39:1731-8
43. Dobson PD, Kell DB. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule?. Nat Rev Drug Discov 2008;7:205-20
44. Armbrecht HJ, Boltz MA, Kumar VB. Intestinal plasma membrane calcium pump protein and its induction by 1, 25 (OH)(2)D(3) decrease with age. Am J Physiol 1999;277:G41-7
45. Toyoshima M, Inada M, Kameyama M. Effects of aging on intracellular transport of vitamin B12 (B12) in rat enterocytes. J Nutr Sci Vitaminol(Tokyo) 1983;29:1-10
46. Russell RM. Changes in gastrointestinal function attributed to aging. Am J Clin Nutr 1992;55:1203S-7S
47. Doherty M, Charman W. The mucosa of the small intestine. Clin Pharmacokinet 2002;41:235-53
48. Gupta S. P-glycoprotein expression and regulation. Age-related changes and potential effects on drug therapy. Drugs Aging 1995;7:19-29
49. ElDesoky ES. Pharmacokinetic-pharmacodynamic crisis in the elderly. Am J Ther 2007;14:488-98
50. 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
51. Wynne H. Drug metabolism and ageing. J Br Menopause Soc 2005;11:51-6
52. Robertson DR, Waller DG, Renwick AG, George CF. Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine. Br J Clin Pharmacol 1988;25:297-305
53. Kelly J, McGarry K, O'Malley K, O'Brien E. Bioavailability of labetalol increases with age. Br J Clin Pharmacol 1982;14:304-5
54. Storstein L, Larsen A, Midtbø K, Saevareid L. Pharmacokinetics of calcium blockers in patients with renal insufficiency and in geriatric patients. Acta Med Scand Suppl 1983;681:25-30
55. Castleden C, George C. The effect of ageing on the hepatic clearance of propranolol. Br J Clin Pharmacol 1979;7:49-54
56. Vestal R, Wood A, Branch R, et al. Effects of age and cigarette smoking on propranolol disposition. Clin Pharmacol Ther 1979;26:8
57. Colangelo PM, Blouin RA, Steinmetz JE, et al. Age and propranolol stereoselective disposition in humans. Clin Pharmacol Ther 1992;51:489-94
58. Schulz P, Turner-Tamiyasu K, Smith G, et al. Amitriptyline disposition in young and elderly normal men. Clin Pharmacol Ther 1983;33:360-6
59. Nation R, Vine J, Triggs E, Learoyd B. Plasma level of chlormethiazole and two metabolites after oral administration to young and aged human subjects. Eur J Clin Pharmacol 1977;12:137-45
60. Taguchi M, Nozawa T, Mizumaki K, et al. Nonlinear mixed effects model analysis of the pharmacokinetics of metoprolol in routinely treated Japanese patients. Biol Pharm Bull 2004;27:1642-8
61. Baillie S, Bateman D, Coates P, Woodhouse K. Age and the pharmacokinetics of morphine. Age Ageing 1989;18:258-62
62. Leenen FH, Coletta E. Pharmacokinetic and antihypertensive profile of amlodipine and felodipine-ER in younger versus older patients with hypertension. J Cardiovasc Pharmacol 2010;56:669-75
63. Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 2007;21:217-30
64. Lees KR, Reid JL. Age and the pharmacokinetics and pharmacodynamics of chronic enalapril treatment. Clin Pharmacol Ther 1987;41:597-602
65. Macdonald N, Sioufi A, Howie C, et al. The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril. Br J Clin Pharmacol 1993;36:205-9
66. Abe M, Smith J, Urae A, et al. Pharmacokinetics of oseltamivir in young and very elderly subjects. Ann Pharmacother 2006;40:1724-30
67. Warrington JS, Greenblatt DJ, von Moltke LL. Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J Pharmacol Exp Ther 2004;309:720-9
68. Palasz A, Wiaderkiewicz A, Wiaderkiewicz R, et al. Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine. Genes Nutr 2012;7:197-207
69. Bolling BW, Blumberg JB, Chen C-YO. Microsomal quercetin glucuronidation in rat small intestine depends on age and segment. Drug Metab Dispos 2011;39:1406-14
70. Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm 2008;65:2347-57
71. Elia M, Stratton R, Holden C, et al. Home artificial nutritional support: the value of the British Artificial Nutrition Survey. Clin Nutr 2001;20:61-6
72. Pironi L, Candusso M, Biondo A, et al Prevalence of home artificial nutrition in Italy in 2005: a survey by the Italian Society for Parenteral and Enteral Nutrition (SINPE). Clin Nutr 2007;26:123-32
73. Magnuson BL, Clifford TM, Hoskins LA, Bernard AC. Enteral nutrition and drug administration, interactions, and complications. Nutr Clin Pract 2005;20:618-24
74. Bauer LA. Interference of oral phenytoin absorption by continuous nasogastric feedings. Neurology 1982;32:570-0
75. Yeung SCA, Ensom MH. Phenytoin and enteral feedings: does evidence support an interaction?. Ann Pharmacother 2000;34:896-905
76. Lubart E, Berkovitch M, Leibovitz A, et al. Phenytoin blood concentrations in hospitalized geriatric patients: oral versus nasogastric feeding tube administration. Ther Drug Monit 2010;32:185-8
77. Lubart E, Berkovitch M, Leibovitz A, et al. Pharmacokinetics of ciprofloxacin in hospitalized geriatric patients: comparison between nasogastric tube and oral administration. Ther Drug Monit 2013;35:653-6
78. Fish DN, Abraham E. Pharmacokinetics of a clarithromycin suspension administered via nasogastric tube to seriously ill patients. Antimicrob Agents Chemother 1999;43:1277-80
79. Mitchell J. Oral dosage forms that should not be crushed. Last update: January 2014 Available from: www.ismp. org/tools/donotcrush.pdf
80. Kaestli LZ, Wasilewski-Rasca AF, Bonnabry P, Vogt-Ferrier N. Use of transdermal drug formulations in the elderly. Drugs Aging 2008;25:269-80
81. Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J Pharmacokinet Biopharm 1989;17:617-30
82. Van Nimmen NF, Poels KL, Menten JJ, et al. Fentanyl transdermal absorption linked to pharmacokinetic characteristics in patients undergoing palliative care. J Clin Pharmacol 2010;50:667-78
83. Konda S, Meier-Davis SR, Cayme B, et al. Age-related percutaneous penetration part 2: effect of age on dermatopharmacokinetics and overview of transdermal products. Skin Therapy Lett 2012;17:5-7
84. Vanakoski J, Seppälä T. Heat exposure and drugs. Clin Pharmacokinet 1998;34:311-22
85. Luebberding S, Krueger N, Kerscher M. Age-related changes in skin barrier function - quantitative evaluation of 150 female subjects. Int J Cosmet Sci 2013;35:183-90
86. Pride N. Ageing and changes in lung mechanics. Eur Respir J 2005;26:563-5
87. Fain SB, Altes TA, Panth SR, et al. Detection of age-dependent changes in healthy adult lungs with diffusionweighted 3He MRI. Acad Radiol 2005;12:1385-93
88. Gupta P, O'Mahony MS. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. Drugs Aging 2008;25:415-43
89. Crompton GK, Barnes PJ, Broeders M, et al. The need to improve inhalation technique in Europe: a report from the aerosol drug management improvement team. Respir Med 2006;100:1479-94
90. Barrons R, Pegram A, Borries A. Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease. Am J Health Syst Pharm 2011;68:1221-32
91. Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-Term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing 2003;32:299-302
92. Ho SF, O'Mahony MS, Steward JA, et al. Inhaler technique in older people in the community. Age Ageing 2004;33:185-8
93. Fulop T Jr, Worum I, Csongor J, et al. Body composition in elderly people. I. Determination of body composition by multiisotope method and the elimination kinetics of these isotopes in healthy elderly subjects. Gerontology 1985;31:6-14
94. Kyle UG, Genton L, Hans D, et al. Total body mass, fat mass, fat-free mass, and skeletal muscle in older people: cross-sectional differences in 60-year-old persons. J Am Geriatr Soc 2001;49:1633-40
95. Hughes VA, Frontera WR, Wood M, et al. Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci 2001;56:B209-17
96. Thompson CM, Johns DO, Sonawane B, et al. Database for physiologically based pharmacokinetic (PBPK) modeling: physiological data for healthy and health-impaired elderly. J Toxicol Environ Health B Crit Rev 2009;12:1-24
97. Hughes VA, Roubenoff R, Wood M, et al. Anthropometric assessment of 10-y changes in body composition in the elderly. Am J Clin Nutr 2004;80:475-82
98. Gába A, Pr?idalová M. Age-related changes in body composition in a sample of Czech women aged 18-89 years: a cross-sectional study. Eur J Nutr 2014;53:167-76
99. Sillanpää E, Cheng S, Häkkinen K, et al. Body composition in 18-To 88-year-old adults - comparison of multifrequency bioimpedance and dual-energy X-ray absorptiometry. Obesity 2014;22:101-9
100. Ravaglia G, Morini P, Forti P, et al. Anthropometric characteristics of healthy Italian nonagenarians and centenarians. Br J Nutr 1997;77:9-17
101. Kuczmarski MF, Kuczmarski RJ, Najjar M. Descriptive anthropometric reference data for older Americans. J Am Diet Assoc 2000;100:59-66
102. Newman AB, Lee JS, Visser M, et al. Weight change and the conservation of lean mass in old age: the health, aging and body composition study. Am J Clin Nutr 2005;82:872-8
103. Mühlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology 1999;45:243-53
104. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002;71:115-21
105. De Vries OJ, Peeters G, Elders P, et al. The elimination half-life of benzodiazepines and fall risk: two prospective observational studies. Age Ageing 2013;42:764-70
106. Fehrman-Ekholm I, Skeppholm L. Renal function in the elderly (70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance. Scand J Urol Nephrol 2004;38:73-7
107. Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging 2001;18:837-51
108. Greenblatt D. Reduced serum albumin concentration in the elderly: a report from the Boston collaborative drug surveillance program. J Am Geriatr Soc 1979;27:20-2
109. 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
110. Chin PKL, Jensen BP, Larsen HS, Begg EJ. Adult age and ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects. Br J Clin Pharmacol 2011;72:985-9
111. Jensen BP, Chin PKL, Roberts RL, Begg EJ. Influence of adult age on the total and free clearance and protein binding of (R)- and (S)-warfarin. Br J Clin Pharmacol 2012;74:797-805
112. Fu A, Nair KS. Age effect on fibrinogen and albumin synthesis in humans. Am J Physiol 1998;275:E1023-30
113. Gunasekera J, Lee D, Jones L, et al. Does albumin fall with increasing age in the absence of disease. Age Ageing 1996;25:P29
114. Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet 2000;38:271-90
115. Butler J, Begg E. Free drug metabolic clearance in elderly people. Clin Pharmacokinet 2008;47:297-321
116. Patterson M, Heazelwood R, Smithurst B, Eadie M. Plasma protein binding of phenytoin in the aged: in vivo studies. Br J Clin Pharmacol 1982;13:423-5
117. Boudinot SG, Funderburg ED, Boudinot FD. Effects of age on the pharmacokinetics of piroxicam in rats. J Pharm Sci 1993;82:254-7
118. 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;37:267-78
119. Cusack B, O'Malley K, Lavan J, et al. Protein binding and disposition of lignocaine in the elderly. Eur J Clin Pharmacol 1985;29:323-9
120. Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet 1994;26:144-60
121. Anders M. Metabolism of drugs by the kidney. Kidney Int 1980;18:636-47
122. Hiraoka H, Yamamoto K, Miyoshi S, et al. Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain. Br J Clin Pharmacol 2005;60:176-82
123. Le Couteur DG, McLean AJ. The aging liver. Clin Pharmacokinet 1998;34:359-73
124. Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 2005;44:33-60
125. 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
126. Zoli M, Magalotti D, Bianchi G, et al. Total and functional hepatic blood flow decrease in parallel with ageing. Age Ageing 1999;28:29-33
127. Zeeh J, Platt D. The aging liver: structural and functional changes and their consequences for drug treatment in old age. Gerontology 2002;48:121-7
128. Woodhouse K, Wynne H. Age-related changes in liver size and hepatic blood flow. Clin Pharmacokinet 1988;15:287-94
129. McLachlan AJ, Pont LG. Drug metabolism in older people - a key consideration in achieving optimal outcomes with medicines. J Gerontol A Biol Sci Med Sci 2012;67:175-80
130. Le Couteur DG, Fraser R, Kilmer S, et al. The hepatic sinusoid in aging and cirrhosis. Clin Pharmacokinet 2005;44:187-200
131. Le Couteur DG, Warren A, Cogger VC, et al. Old age and the hepatic sinusoid. Anat Rec 2008;291:672-83
132. Hilmer SN, Cogger VC, Fraser R, et al. Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat. Hepatology 2005;42:1349-54
133. Hilmer SN, Cogger VC, Muller M, Le Couteur DG. The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin. Drug Metab Dispos 2004;32:794-9
134. Mitchell SJ, Huizer-Pajkos A, Cogger VC, et al. Age-related pseudocapillarization of the liver sinusoidal endothelium impairs the hepatic clearance of acetaminophen in rats. J Gerontol A Biol Sci Med Sci 2011;66A:400-8
135. Mitchell SJ, Huizer-Pajkos A, Cogger VC, et al. The influence of old age and poloxamer-407 on the hepatic disposition of diazepam in the isolated perfused rat liver. Pharmacology 2012;90:233-41
136. Parkinson A, Mudra DR, Johnson C, et al. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol 2004;199:193-209
137. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions[ast]. Clin Pharmacol Ther 1997;61:331-9
138. 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;59:155-65
139. Bebia Z, Buch SC, Wilson JW, et al. Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 2004;76:618-27
140. Schmucker DL. Age-related changes in liver structure and function: implications for disease?. Exp Gerontol 2005;40:650-9
141. Twum-Barima Y, Finnigan T, Habash AI, et al. Impaired enzyme induction by rifampicin in the elderly. Br J Clin Pharmacol 1984;17:595-7
142. Kinirons M, O'Mahony M. Drug metabolism and ageing. Br J Clin Pharmacol 2004;57:540-4
143. Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother 2011;9:364-77
144. Fromm MF, Dilger K, Busse D, et al. Gut wall metabolism of verapamil in older people: effects of rifampicinmediated enzyme induction. Br J Clin Pharmacol 1998;45:247-55
145. 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;32:768-70
146. Court MH. Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metab Rev 2010;42:209-24
147. Divoll M, Greenblatt DJ, Harmatz JS, Shader RI. Effect of age and gender on disposition of temazepam. J Pharm Sci 1981;70:1104-7
148. Ghabrial H, Desmond P, Watson K, et al. The effects of age and chronic liver disease on the elimination of temazepam. Eur J Clin Pharmacol 1986;30:93-7
149. Smith R, Divoll M, Gillespie W, Greenblatt D. Effect of subject age and gender on the pharmacokinetics of oral triazolam and temazepam. J Clin Psychopharmacol 1983;3:172-5
150. Wynne HA, Cope LH, Herd B, et al. The association of age and frailty with paracetamol conjugation in man. Age Ageing 1990;19:419-24
151. Wynne H, Yelland C, Cope L, et al. The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide. Age Ageing 1993;22:354-9
152. Williams F, Wynne H, Woodhouse K, Rawlins M. Plasma aspirin esterase: the influence of old age and frailty. Age Ageing 1989;18:39-42
153. Mitchell SJ, Kane AE, Hilmer SN. Age-related changes in the hepatic pharmacology and toxicology of paracetamol. Curr Gerontol Geriatr Res 2011;2011:624156
154. Fliser D, Franek E, Ritz E. Renal function in the elderly-is the dogma of an inexorable decline of renal function correct?. Nephrol Dial Transplant 1997;12:1553-5
155. Sesso R, Prado F, Vicioso B, Ramos LR. Prospective study of progression of kidney dysfunction in communitydwelling older adults. Nephrology 2008;13:99-103
156. Tsaih S-W, Korrick S, Schwartz J, et al. Lead, diabetes, hypertension, and renal function: the normative aging study. Environ Health Perspect 2004;112(11):1178-82
157. Loboz KK, Shenfield GM. Drug combinations and impaired renal function-The 'triple whammy'. Br J Clin Pharmacol 2005;59:239-43
158. Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with nonsteroidal anti-inflammatory drugs and risk of acute kidney injury: nested casecontrol study. BMJ 2013;346:e8525
159. Lindeman R, Tobin J, Shock N. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33:278-85
160. Aymanns C, Keller F, Maus S, et al. Review on pharmacokinetics and pharmacodynamics and the aging kidney. Clin J Am Soc Nephrol 2010;5:314-27
161. Keller F, Frankewitsch T, Zellner D, et al. Standardized structure and modular design of a pharmacokinetic database. Comput Methods Programs Biomed 1998;55:107-15
162. Fliser D, Zeier M, Nowack R, Ritz E. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol 1993;3:1371-7
163. Esposito C, Plati A, Mazzullo T, et al. Renal function and functional reserve in healthy elderly individuals. J Nephrol 2007;20:617-25
164. Schmitt R, Coca S, Kanbay M, et al. Recovery of kidney function after acute kidney injury in the elderly: a systematic review and meta-analysis. Am J Kidney Dis 2008;52:262-71
165. Johnston C, Hilmer S, McLachlan A, et al. The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration. Eur J Clin Pharmacol 2014;70:549-55
166. Lionakis N, Mendrinos D, Sanidas E, et al. Hypertension in the elderly. World J Cardiol 2012;4:135
167. Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care 2012;35:2650-64
168. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038-47
169. Lassiter J, Bennett WM, Olyaei AJ. Drug Dosing in Elderly Patients with Chronic Kidney Disease. Clin Geriatr Med 2013;29:657-705
170. Stevens LA, Padala S, Levey AS. Advances in glomerular filtration rate estimating equations. Curr Opin Nephrol Hypertens 2010;19:298
171. Stevens LA, Schmid CH, Greene T, et al. Comparative performance of the CKD epidemiology collaboration (CKDEPI) and the modification of diet in renal disease (MDRD) study equations for estimating GFR levels Above 60 mL/min/1.73m2. Am J Kidney Dis 2010;56:486-95
172. Van Bemmel T, Woittiez K, Blauw GJ, et al. Prospective study of the effect of blood pressure on renal function in old age: the Leiden 85-plus study. J Am Soc Nephrol 2006;17:2561-6
173. Nolin T, Naud J, Leblond F, Pichette V. Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther 2008;83:898-903
174. Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol 2008;4:1065-74
175. Barnes KJ, Rowland A, Polasek TM, Miners JO. Inhibition of human drugmetabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins. Eur J Clin Pharmacol 2014;70:1097-106
176. Naud J, Michaud J, Beauchemin S, et al. Effects of chronic renal failure on kidney drug transporters and cytochrome P450 in rats. Drug Metab Dispos 2011;39:1363-9
177. Delgado-Guay MO, Bruera E. Management of pain in the older person with cancer. Oncology (Williston Park) 2008;22:56-61
178. Plummer JL, Gourlay GK, Cherry DA, Cousins MJ. Estimation of methadone clearance: application in the management of cancer pain. Pain 1988;33:313-22
179. Modesto-Lowe V, Brooks D, Petry N. Methadone deaths: risk factors in pain and addicted populations. J Gen Intern Med 2010;25:305-9
180. Polasek TM, Patel F, Jensen BP, et al. Predicted metabolic drug clearance with increasing adult age. Br J Clin Pharmacol 2013;75:1019-28
181. Strougo A, Yassen A, Krauwinkel W, et al. A semiphysiological population model for prediction of the pharmacokinetics of drugs under liver and renal disease conditions. Drug Metab Dispos 2011;39:1278-87