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Drugs and the ageing liver
JournalofHepatology, 1985;1:431-435
431
Elsevier
HEP 0043
Review
Drugs and the Ageing Liver O. F. W. James* Geriatric~Medical Unit 1, Freeman Hospital, Newcastle upon Tyne ( U. K. )
Introduction A recent WHO estimate suggests that ca. 20% of the population in developed countries are 'elderly' and that 50% of all drugs are prescribed to individuals over age 65 years. It is now well recognised that the elderly are particularly susceptible to drug adverse reactions in general [1-3], and there are increasing suggestions that 'a number of hepatic adverse reactions to drugs may be age-related [4,5]. It is therefore appropriate to examine the changes which occur in human hepatic drug metabolism in advanced age and to assess the evidence for increased sensitivity to hepatic .adverse drug reactions in the elderly. The important liver-related physiological changes which may affect hepatic disposition of drugs which advanced age include reduced liver blood flow, and progressive decrease in liver size and weight both absolutely and relative to total body weight [6]. Other age-related changes which may affect drug pharmacokinetics include decrease in lean body mass with a proportionate increase in fat; glomerular filtration rate declines by 1-2% per year over age 65.
Hepatic Metabolism of Drugs Many studies of the pharmacokinetics of individual drugs in relation to age have now been carried out. These have been well summarised by Greenblatt et al. [7] and Klotz and Bruckel [8]. The weight of these studies suggests that there is an agerelated reduction in hepatic clearance of many drugs metabolised by oxidation or reduction, although this is by no means true of all drugs in this group. Thus, for ex* Readerin Medicine,Universityof NewcastleUponTyne. 0168-8278/85/$03.30 © 1985ElsevierSciencePublishersB.V. (BiomedicalDivision)
432
o . F . W . JAMES
ample chlordiazepoxide [9], quinidine [10], and theophylline [11] show reduced hepatic metabolism whereas digitoxin [12] and prazocin [13] do not. Where there is impaired metabolism of these drugs their diposition and elimination with advanced age is strikingly similar to that seen in cirrhosis. Thus Roberts et al. [9] found that there was a marked increased elimination half life of chlordiazepoxide in both the elderly and in cirrhotics, in each case attributable to reduced plasma clearance and increased volume of distribution. Although it has been implied that the reduced hepatic clearance of such drugs was due to a reduction in the hepatic microsomal enzyme activities responsible for their metabolism [7] no age-related reduction in the specific activities of the only three microsomal mono-oxygenases measured in human liver has been found [14,15]. If the specific activities of the microsomal enzymes responsible for the metabolism of the drugs in which age-related impairment of pharmacokinetics has been found are indeed not decreased the reduction of liver size and thus of total metabolic capacity may be critical. Conceivably while the specific activity of the metabolic enzymes is unimpaired their affinity for the drug substrates may be altered with advancing age. This hypothesis has yet to be tested in man. Although the biotransformation of some drugs via phase I reactions may thus be impaired the majority of phase II (conjugation) reactions are unaffected by advanced age. Thus acetylation of isoniazid [16] and glucuronidation of temazepam [17] are not reduced. It has been suggested that there is an impaired ability to induce hepatic mono-oxygenase enzyme activity in the elderly. The recent study of Pearson and Roberts [18] has clearly shown that the potent enzyme inducer glutethimide does increase the hepatic metabolism of the model dru.g antipyrine by 75 % in normal elderly subjects. Thus studies of age-related changes in pharmacokinetics must take such factors as alterations in medication, diet and particularly smoking and alcohol consumption into account. Although it is widely stated and accepted that hepatic blood flow declines with age from ca. 1500 ml/min age 30 to less than 1000 ml/min over age 65 [6] modern studies to confirm this decline are lacking. Since liver blood flow is the major determinant of total clearance of highly extracted drugs it would be expected that this group would have marked impairment of first pass effect in the elderly and thus greater bioavailability. This is indeed the case with such high clearance drugs as labetolol, propranolol, lignocaine and chlormethiazole [19,20]. Since many drugs are extensively bound to albumin [7] or al-acid glycoprotein [21] then age-related alterations in serum albumin - - usually slightly reduced with increased age, or a~-acid glycoprotein - - usually elevated at advanced age, may be important determinants of free drug clearance. In practice such alterations have not been clearly shown to be clinically important, but in the elderly, as in cirrhotics, the free fraction of diazepam is markedly increased thus possibly contributing to its enhanced and prolonged clinical effect in these two groups [22]. In contrast propranolol binding to al-acid glycoprotein is increased in healthy elderly individuals and markedly so in sick old people thus theoretically leading to a reduced clinical efficacy [21].
DRUGS AND THE AGEING LIVER
433.
Age-Related Hepatic Adverse Reactions Considerable attention has been focused on the possibility that some serious hepatic adverse drug reactions may be age-related since the reports of Taggart and Alderdice [23] and Goudie et al. [24] drew attention to fatal cholestatic jaundice in elderly patients receiving the non-steroidal anti-inflammatory drug (NSAID) benoxaprofen. Of 9 patients reported by these two groups 6 were over age 80, the remaining 3 were over 70. Furthermore Halsey and Cardoe [25], documenting all adverse reactions to benoxaprofen, showed that 8.1% of individuals taking the drug under age 70 experienced gastro-intestinal side-effects vs 31.9% of those over age 70. The exact mechanism by which the severe hepatic reactions were mediated is not clear. Many of the elderly patients also had renal impairment and since benoxaprofen is normally excreted unchanged via the kidneys it has been suggested that a higher proportion of the drug was excreted via a biliary pathway. The typical biliary concretions seen on liver histology possibly representing unchanged benoxaprofen or a conjugate (Macsween, R., personal communication; Hofmann, A. F., personal communication). It is perhaps of interest that of the 36 drugs most commonly suspect of hepatic adverse reactions in Britain 9 (one quarter) are NSAIDs whose predominant use is in the elderly. Since such a high proportion of all drug usage is in the elderly it is extremely difficult, however, to confidently assert that such adverse reactions are age-related. Table 1 shows a list of drugs with well-recognised hepatic adverse reactions in which age has been associated with the occurrence of these events. It is difficult to draw any firm conclusions from these studies since the drugs are very heterogeneous and the putative mechanisms of liver damage vary. In every case there is some evidence, usually indirect, to suggest that a toxic metabolite may at least in part be responsible for the production of liver damage even if in the cases of ticrynafen, methyldopa and halothane an immune mechanism may also be partly incriminated. It is not therefore clear at present whether some age-related increase in metabolic pathways leading to possible toxic metabolites or age-related alteration in the im-
TABLE 1 DRUGS IN WHICH HEPATIC ADVERSE REACTION HAS BEEN PROBABLY SHOWN TO BE AGE-RELATED Drug
Reaction
Other features
Reference
Ticrynafen Ketoconazole Methyldopa Halothane
Acute hepatitis/CAH Hepatic necrosis Acute hepatitis/CAH Hepatitis/FHF
Mainly women Mainly women
Benoxaprofen
Cholestasis
Often renal impairment
Dantrolene
Hepatocellular
All deaths over age 30
Zimmerman et al. [4] Lewis et al. [5] Rodman et al. [26] Neuberger and Williams [27]; Inman and Mushin [28] Taggart and Alderdice [23]; Goudie et al. [24] Utili et ai. [29]
Mainly women
434
o.F.W. JAMES
mune response may be causally related to these hepatic reactions. Clearly further evaluation of the role of age per se in the pathoetiology of these reactions is needed. .Since we are only now becoming aware that age probably constitutes an independent risk factor in hepatic adverse drug reactions this has not been taken into account in many earlier reports and analyses. In this context it is of interest that whereas only ca. 2% of reported adverse drug reactions in the U.K. are liver-related in individuals under age 14, the proportion of liver reactions rises to ca. 5% of the total in over 70 year olds (DHSS, unpublished data). In addition to increased age-related risk of adverse reactions there is an increased risk of mortality in older individuals if liver damage has occurred in the cases of halothane and dantrolene; this is probably also true of paracetamol (acetaminophen) overdose although this is poorly documented. In the United Kingdom there is a steadily increasing risk of mortality from reported hepatic drug reactions with increasing age from less than 5% age 15-24 years to over 20% age over 70 years (DHSS, unpublished data). The reason for this increased mortality with advanced age is not clear but D-galactosamine-induced hepatic necrosis is much more severe in old than in young rats [30]. It is attractive to speculate that this increased susceptibility to m o ~ severe liver damage might be due therefore to inadequate activity of detoxification pathways in the old liver. In the only study to examine these metabolic pathways in ageing man no such impairment of epoxide hydrolase activity or glutathione concentration (two agents of detoxification) has been observed [151. Finally, drug regulatory bodies in Europe and the U.S.A. are now increasingly aware both of the alterations in pharmacokinetics and pharmacodynamics of drugs which occur in the elderly and of the need to specifically monitor age-related drug toxicity. Such surveillance ma3/soon lead to a more intelligent understanding of the reactions which I have discussed and hence to the prevention of similar drug-related morbidity and mortality in the future.
References 1 Hurwitz,N., Predisposingfactorsto adversereactionsto drugs, Brit. IVied.J., 1969;I: 536-539. 2 Vestal, R. E., Drug use in the elderly -- A review of problems and special considerations,Drugs, 1978; 16: 358-382. 3 Williamson,J. and Chopin, J. M., Adverse reactions to prescribed drugs in the elderly- - A multicentre investigation,Age and Ageing, 1980;9: 73-80. 4 Zimmerman,H. J., Lewis,J. H., Ishak, K. G. and Maddrey, W. C., Trierynafen-associatedhepatic injury-- Analysisof 340 cases, Hepatology, 1984;4: 315-323, 5 Lewis,J. H., Zimmerman, H. J., Benson, G. D. and Ishak, K. G., Hepatic injury associatedwith Ketoconazoletherapy, Gastroenterology,1984; 86: 503-513. 6 James, O. F. W., Gastrointestinal and liver function in old age, Clin. Oastroenterol., 1983; 12: 671-691. 7 Greenblatt, D. J., Sellers, E. M. and Shader, R. I., Drug dispositionin old age, N. Engl. J. Med., 1982; 306: 1081-1088. 8 Klotz, U. and Bruckel, K. W., Pharmacokineticsand pharmacodynamicsin the elderly. In: K. Kitani (Ed.), Liver and Ageing-- 1982, Elsevier, Amsterdam, pp. 287-301. 9 Roberts, R. K., Wilkinson,G. R., Branch, R. A. and Schenker, S., Effect of age and parenchymal
DRUGS AND THE AGEING LIVER
435
liver disease on the disposition and elimination of chlordiazepoxide, Gastroenterology, 1978; 75: 479-485. 10 Ochs, H. R., Greenblatt, D. J., Woo, E. and Smith, T. W., Reduced quinidine clearance in elderly persons, Amer. J. Cardiol., 1978; 42: 481-485. 11 Antal, E. J., Kramer, P. A., Mercik, S. A., Chapron, D. J. and Lawson, I. R., Theophylline pharmacokinetics in advanced age, Brit. J. Clin. Pharmacol., 1981; 12: 637-645. 12 Donovan, M. A., Castleden, C. M., Pohl, J. E. F. and Kraft, C. A., The effect of age on digitoxin pharmaeokinetics, Brit. J. Clin. Pharmacol., 1981; 11: 287-294. 13 Rubin, P. C., Scott, P. J. W. and Reid, J. L., Prazocin disposition in young and elderly subjects, Brit. J. Clin. Pharmacol., 1981; 12: 401-404. 14 Brodie, M. J., Boobis, A. R., Bulpitt, C. J. and Davies, D. S., Influence of liver disease and environmental factors on hepatic mono-oxygenase activity in vitro, Europ. J. Clin. Pharmacol., 1981; 20: 39-46. 15 Woodhouse, K. W., Mutch, E., Williams, F. M., Rawlins, M. D. and James, O. F. W., The effect of age on pathways of drug metabolism in human liver, Age and Ageing, 1984; 13: 321-328. 16 Farah, F., Taylor, W., Rawiins, M. D. and James, O. F. W., Hepatic drug acetylation and oxidation --Effects of ageing in man, Brit. IVied.J., 1977; II: 155-156. 17 Divoli, M., Greenblatt, D. J., Harmatz, J. S. and Shader, R. I., Effect of age and gender on the disposition of temazepam, J. Pharm Sci., 1981; 70: 1104-1107. 18 Pearson, M. W. and Roberts, C. J. C., Drug induction of hepatic enzymes in the elderly, Age and Ageing, 1984; 13: 313-316. 19 O'Malley, K. and Kelly, J., Recent pharmacokinetic studies of metabolised drugs in the elderly. In: K. Kitani (Ed.), Liver and Ageing-- 1982, Elsevier, Amsterdam, pp. 303-312. 20 Feely, J., Crooks, J. and Stevenson, I. H., The influence of age, smoking and hyperthyroidism on plasma propranolol steady state concentration, Brit. J. Clin. Pharmacol., 1981; 12: 731-780. 21 Paxton, J. W. and Briant, R. H., al-Aeid glycoprotein concentrations and propranolol binding in elderly patients with acute illness, Brit. J. Clln. Pharmacol., 1984; 18: 806-810. 22 Macklon, A. F., Barton, M., James, O. F. W. and Rawlins, M. D., The effect of age on the pharmaeokinetics of diazepam, Clin. Sci., 1980; 59: 479-483. 23 Taggart, H. McA. and Alderdice, J. M., Fatal cholestatic jaundice in elderly persons taking benoxaprofen, Brit. Med. J., 1982; 284: 1372. 24 Goudie, B. M., Birnie, G. F., Watkinson, G., et al., Jaundice associated with the use of benoxaprofen, Lancet, 1982; i: 959. 25 Halsey, J. P. and Cardoe, N., Gastrointestinal haemorrhage and banoxaprofen, Brit. Med. J., 1982; I: 508. 26 Rodman, J. S., Deutsch, D. J. and Gutman, S. I., Methyldopa hepatitis w A report of six eases and review of the literature, Amer. J. Med., 1976; 60: 941-948. 27 Neuberger, J. and Williams, R., Halothane anaesthesia and liver damage, Brit. Med. J., 1984; IV: 1136-1139. 28 Inman, W. H. W. and Mushin, W. W., Jaundice after repeated exposure to halothane - - A further analysis of reports to the Committee on Safety of Medicines, Brit. Ivied. J., 1978; II: 1455-1456. 29 Utili, R., Boitnott, J. and Zimmerman, H. J., Dantrolene-associated hepatic injury, Gastroenterology, 1977; 72: 610-616. 30 Platt, D., Age dependent morphological and biochemical studies of the normal and injured rat liver. In: D. Platt (Ed.), Liver and Ageing-- 1977, F. K. Schattnauer, Stuttgart, pp. 75-83.
431
Elsevier
HEP 0043
Review
Drugs and the Ageing Liver O. F. W. James* Geriatric~Medical Unit 1, Freeman Hospital, Newcastle upon Tyne ( U. K. )
Introduction A recent WHO estimate suggests that ca. 20% of the population in developed countries are 'elderly' and that 50% of all drugs are prescribed to individuals over age 65 years. It is now well recognised that the elderly are particularly susceptible to drug adverse reactions in general [1-3], and there are increasing suggestions that 'a number of hepatic adverse reactions to drugs may be age-related [4,5]. It is therefore appropriate to examine the changes which occur in human hepatic drug metabolism in advanced age and to assess the evidence for increased sensitivity to hepatic .adverse drug reactions in the elderly. The important liver-related physiological changes which may affect hepatic disposition of drugs which advanced age include reduced liver blood flow, and progressive decrease in liver size and weight both absolutely and relative to total body weight [6]. Other age-related changes which may affect drug pharmacokinetics include decrease in lean body mass with a proportionate increase in fat; glomerular filtration rate declines by 1-2% per year over age 65.
Hepatic Metabolism of Drugs Many studies of the pharmacokinetics of individual drugs in relation to age have now been carried out. These have been well summarised by Greenblatt et al. [7] and Klotz and Bruckel [8]. The weight of these studies suggests that there is an agerelated reduction in hepatic clearance of many drugs metabolised by oxidation or reduction, although this is by no means true of all drugs in this group. Thus, for ex* Readerin Medicine,Universityof NewcastleUponTyne. 0168-8278/85/$03.30 © 1985ElsevierSciencePublishersB.V. (BiomedicalDivision)
432
o . F . W . JAMES
ample chlordiazepoxide [9], quinidine [10], and theophylline [11] show reduced hepatic metabolism whereas digitoxin [12] and prazocin [13] do not. Where there is impaired metabolism of these drugs their diposition and elimination with advanced age is strikingly similar to that seen in cirrhosis. Thus Roberts et al. [9] found that there was a marked increased elimination half life of chlordiazepoxide in both the elderly and in cirrhotics, in each case attributable to reduced plasma clearance and increased volume of distribution. Although it has been implied that the reduced hepatic clearance of such drugs was due to a reduction in the hepatic microsomal enzyme activities responsible for their metabolism [7] no age-related reduction in the specific activities of the only three microsomal mono-oxygenases measured in human liver has been found [14,15]. If the specific activities of the microsomal enzymes responsible for the metabolism of the drugs in which age-related impairment of pharmacokinetics has been found are indeed not decreased the reduction of liver size and thus of total metabolic capacity may be critical. Conceivably while the specific activity of the metabolic enzymes is unimpaired their affinity for the drug substrates may be altered with advancing age. This hypothesis has yet to be tested in man. Although the biotransformation of some drugs via phase I reactions may thus be impaired the majority of phase II (conjugation) reactions are unaffected by advanced age. Thus acetylation of isoniazid [16] and glucuronidation of temazepam [17] are not reduced. It has been suggested that there is an impaired ability to induce hepatic mono-oxygenase enzyme activity in the elderly. The recent study of Pearson and Roberts [18] has clearly shown that the potent enzyme inducer glutethimide does increase the hepatic metabolism of the model dru.g antipyrine by 75 % in normal elderly subjects. Thus studies of age-related changes in pharmacokinetics must take such factors as alterations in medication, diet and particularly smoking and alcohol consumption into account. Although it is widely stated and accepted that hepatic blood flow declines with age from ca. 1500 ml/min age 30 to less than 1000 ml/min over age 65 [6] modern studies to confirm this decline are lacking. Since liver blood flow is the major determinant of total clearance of highly extracted drugs it would be expected that this group would have marked impairment of first pass effect in the elderly and thus greater bioavailability. This is indeed the case with such high clearance drugs as labetolol, propranolol, lignocaine and chlormethiazole [19,20]. Since many drugs are extensively bound to albumin [7] or al-acid glycoprotein [21] then age-related alterations in serum albumin - - usually slightly reduced with increased age, or a~-acid glycoprotein - - usually elevated at advanced age, may be important determinants of free drug clearance. In practice such alterations have not been clearly shown to be clinically important, but in the elderly, as in cirrhotics, the free fraction of diazepam is markedly increased thus possibly contributing to its enhanced and prolonged clinical effect in these two groups [22]. In contrast propranolol binding to al-acid glycoprotein is increased in healthy elderly individuals and markedly so in sick old people thus theoretically leading to a reduced clinical efficacy [21].
DRUGS AND THE AGEING LIVER
433.
Age-Related Hepatic Adverse Reactions Considerable attention has been focused on the possibility that some serious hepatic adverse drug reactions may be age-related since the reports of Taggart and Alderdice [23] and Goudie et al. [24] drew attention to fatal cholestatic jaundice in elderly patients receiving the non-steroidal anti-inflammatory drug (NSAID) benoxaprofen. Of 9 patients reported by these two groups 6 were over age 80, the remaining 3 were over 70. Furthermore Halsey and Cardoe [25], documenting all adverse reactions to benoxaprofen, showed that 8.1% of individuals taking the drug under age 70 experienced gastro-intestinal side-effects vs 31.9% of those over age 70. The exact mechanism by which the severe hepatic reactions were mediated is not clear. Many of the elderly patients also had renal impairment and since benoxaprofen is normally excreted unchanged via the kidneys it has been suggested that a higher proportion of the drug was excreted via a biliary pathway. The typical biliary concretions seen on liver histology possibly representing unchanged benoxaprofen or a conjugate (Macsween, R., personal communication; Hofmann, A. F., personal communication). It is perhaps of interest that of the 36 drugs most commonly suspect of hepatic adverse reactions in Britain 9 (one quarter) are NSAIDs whose predominant use is in the elderly. Since such a high proportion of all drug usage is in the elderly it is extremely difficult, however, to confidently assert that such adverse reactions are age-related. Table 1 shows a list of drugs with well-recognised hepatic adverse reactions in which age has been associated with the occurrence of these events. It is difficult to draw any firm conclusions from these studies since the drugs are very heterogeneous and the putative mechanisms of liver damage vary. In every case there is some evidence, usually indirect, to suggest that a toxic metabolite may at least in part be responsible for the production of liver damage even if in the cases of ticrynafen, methyldopa and halothane an immune mechanism may also be partly incriminated. It is not therefore clear at present whether some age-related increase in metabolic pathways leading to possible toxic metabolites or age-related alteration in the im-
TABLE 1 DRUGS IN WHICH HEPATIC ADVERSE REACTION HAS BEEN PROBABLY SHOWN TO BE AGE-RELATED Drug
Reaction
Other features
Reference
Ticrynafen Ketoconazole Methyldopa Halothane
Acute hepatitis/CAH Hepatic necrosis Acute hepatitis/CAH Hepatitis/FHF
Mainly women Mainly women
Benoxaprofen
Cholestasis
Often renal impairment
Dantrolene
Hepatocellular
All deaths over age 30
Zimmerman et al. [4] Lewis et al. [5] Rodman et al. [26] Neuberger and Williams [27]; Inman and Mushin [28] Taggart and Alderdice [23]; Goudie et al. [24] Utili et ai. [29]
Mainly women
434
o.F.W. JAMES
mune response may be causally related to these hepatic reactions. Clearly further evaluation of the role of age per se in the pathoetiology of these reactions is needed. .Since we are only now becoming aware that age probably constitutes an independent risk factor in hepatic adverse drug reactions this has not been taken into account in many earlier reports and analyses. In this context it is of interest that whereas only ca. 2% of reported adverse drug reactions in the U.K. are liver-related in individuals under age 14, the proportion of liver reactions rises to ca. 5% of the total in over 70 year olds (DHSS, unpublished data). In addition to increased age-related risk of adverse reactions there is an increased risk of mortality in older individuals if liver damage has occurred in the cases of halothane and dantrolene; this is probably also true of paracetamol (acetaminophen) overdose although this is poorly documented. In the United Kingdom there is a steadily increasing risk of mortality from reported hepatic drug reactions with increasing age from less than 5% age 15-24 years to over 20% age over 70 years (DHSS, unpublished data). The reason for this increased mortality with advanced age is not clear but D-galactosamine-induced hepatic necrosis is much more severe in old than in young rats [30]. It is attractive to speculate that this increased susceptibility to m o ~ severe liver damage might be due therefore to inadequate activity of detoxification pathways in the old liver. In the only study to examine these metabolic pathways in ageing man no such impairment of epoxide hydrolase activity or glutathione concentration (two agents of detoxification) has been observed [151. Finally, drug regulatory bodies in Europe and the U.S.A. are now increasingly aware both of the alterations in pharmacokinetics and pharmacodynamics of drugs which occur in the elderly and of the need to specifically monitor age-related drug toxicity. Such surveillance ma3/soon lead to a more intelligent understanding of the reactions which I have discussed and hence to the prevention of similar drug-related morbidity and mortality in the future.
References 1 Hurwitz,N., Predisposingfactorsto adversereactionsto drugs, Brit. IVied.J., 1969;I: 536-539. 2 Vestal, R. E., Drug use in the elderly -- A review of problems and special considerations,Drugs, 1978; 16: 358-382. 3 Williamson,J. and Chopin, J. M., Adverse reactions to prescribed drugs in the elderly- - A multicentre investigation,Age and Ageing, 1980;9: 73-80. 4 Zimmerman,H. J., Lewis,J. H., Ishak, K. G. and Maddrey, W. C., Trierynafen-associatedhepatic injury-- Analysisof 340 cases, Hepatology, 1984;4: 315-323, 5 Lewis,J. H., Zimmerman, H. J., Benson, G. D. and Ishak, K. G., Hepatic injury associatedwith Ketoconazoletherapy, Gastroenterology,1984; 86: 503-513. 6 James, O. F. W., Gastrointestinal and liver function in old age, Clin. Oastroenterol., 1983; 12: 671-691. 7 Greenblatt, D. J., Sellers, E. M. and Shader, R. I., Drug dispositionin old age, N. Engl. J. Med., 1982; 306: 1081-1088. 8 Klotz, U. and Bruckel, K. W., Pharmacokineticsand pharmacodynamicsin the elderly. In: K. Kitani (Ed.), Liver and Ageing-- 1982, Elsevier, Amsterdam, pp. 287-301. 9 Roberts, R. K., Wilkinson,G. R., Branch, R. A. and Schenker, S., Effect of age and parenchymal
DRUGS AND THE AGEING LIVER
435
liver disease on the disposition and elimination of chlordiazepoxide, Gastroenterology, 1978; 75: 479-485. 10 Ochs, H. R., Greenblatt, D. J., Woo, E. and Smith, T. W., Reduced quinidine clearance in elderly persons, Amer. J. Cardiol., 1978; 42: 481-485. 11 Antal, E. J., Kramer, P. A., Mercik, S. A., Chapron, D. J. and Lawson, I. R., Theophylline pharmacokinetics in advanced age, Brit. J. Clin. Pharmacol., 1981; 12: 637-645. 12 Donovan, M. A., Castleden, C. M., Pohl, J. E. F. and Kraft, C. A., The effect of age on digitoxin pharmaeokinetics, Brit. J. Clin. Pharmacol., 1981; 11: 287-294. 13 Rubin, P. C., Scott, P. J. W. and Reid, J. L., Prazocin disposition in young and elderly subjects, Brit. J. Clin. Pharmacol., 1981; 12: 401-404. 14 Brodie, M. J., Boobis, A. R., Bulpitt, C. J. and Davies, D. S., Influence of liver disease and environmental factors on hepatic mono-oxygenase activity in vitro, Europ. J. Clin. Pharmacol., 1981; 20: 39-46. 15 Woodhouse, K. W., Mutch, E., Williams, F. M., Rawlins, M. D. and James, O. F. W., The effect of age on pathways of drug metabolism in human liver, Age and Ageing, 1984; 13: 321-328. 16 Farah, F., Taylor, W., Rawiins, M. D. and James, O. F. W., Hepatic drug acetylation and oxidation --Effects of ageing in man, Brit. IVied.J., 1977; II: 155-156. 17 Divoli, M., Greenblatt, D. J., Harmatz, J. S. and Shader, R. I., Effect of age and gender on the disposition of temazepam, J. Pharm Sci., 1981; 70: 1104-1107. 18 Pearson, M. W. and Roberts, C. J. C., Drug induction of hepatic enzymes in the elderly, Age and Ageing, 1984; 13: 313-316. 19 O'Malley, K. and Kelly, J., Recent pharmacokinetic studies of metabolised drugs in the elderly. In: K. Kitani (Ed.), Liver and Ageing-- 1982, Elsevier, Amsterdam, pp. 303-312. 20 Feely, J., Crooks, J. and Stevenson, I. H., The influence of age, smoking and hyperthyroidism on plasma propranolol steady state concentration, Brit. J. Clin. Pharmacol., 1981; 12: 731-780. 21 Paxton, J. W. and Briant, R. H., al-Aeid glycoprotein concentrations and propranolol binding in elderly patients with acute illness, Brit. J. Clln. Pharmacol., 1984; 18: 806-810. 22 Macklon, A. F., Barton, M., James, O. F. W. and Rawlins, M. D., The effect of age on the pharmaeokinetics of diazepam, Clin. Sci., 1980; 59: 479-483. 23 Taggart, H. McA. and Alderdice, J. M., Fatal cholestatic jaundice in elderly persons taking benoxaprofen, Brit. Med. J., 1982; 284: 1372. 24 Goudie, B. M., Birnie, G. F., Watkinson, G., et al., Jaundice associated with the use of benoxaprofen, Lancet, 1982; i: 959. 25 Halsey, J. P. and Cardoe, N., Gastrointestinal haemorrhage and banoxaprofen, Brit. Med. J., 1982; I: 508. 26 Rodman, J. S., Deutsch, D. J. and Gutman, S. I., Methyldopa hepatitis w A report of six eases and review of the literature, Amer. J. Med., 1976; 60: 941-948. 27 Neuberger, J. and Williams, R., Halothane anaesthesia and liver damage, Brit. Med. J., 1984; IV: 1136-1139. 28 Inman, W. H. W. and Mushin, W. W., Jaundice after repeated exposure to halothane - - A further analysis of reports to the Committee on Safety of Medicines, Brit. Ivied. J., 1978; II: 1455-1456. 29 Utili, R., Boitnott, J. and Zimmerman, H. J., Dantrolene-associated hepatic injury, Gastroenterology, 1977; 72: 610-616. 30 Platt, D., Age dependent morphological and biochemical studies of the normal and injured rat liver. In: D. Platt (Ed.), Liver and Ageing-- 1977, F. K. Schattnauer, Stuttgart, pp. 75-83.