Archives of Gerontology and Geriatrics
32 (2001) 255– 263
www.elsevier.com/locate/archger

The aging liver: consequences for drug
treatment in old age
J. Zeeh
Geriatrische Fachklinik Georgenhaus, D-98617 Meiningen, Germany
Received 29 November 2000; received in revised form 25 February 2001; accepted 26 February 2001

Abstract
Numerous age-related changes in hepatic structure and function have been described
although liver function seems to be quite well maintained in old age. Few consistent and
reproducible observations and a lack of correlation between structural and functional data
characterize the present state of our knowledge. However, a decline in liver volume and
blood flow has been shown in older subjects, which is the physiologic basis of reduced
hepatic drug clearance in this age group. In contrast to renal clearance, no reliable method
exists to estimate hepatic drug clearance. The contribution of age to altered drug clearance
in the elderly is difficult to assess as drug interactions, numbers and types of drugs taken at
a time, underlying disease and increased interindividual variability are superimposed to the
aging process. Therefore, after decades of research into the matter, the old and well known
aphorism ‘start lower — go slower’ is valid more than ever in the field of geriatric
prescribing. Not only renally excreted drugs but also substances metabolized and excreted by
the liver should be used in a starting dose which is 30 – 40% smaller than the average dose
used in middle aged adults. © 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Aging of liver; Drug metabolization in old liver; Hepatic detoxification

1. Introduction
Due to age-associated changes and the sequelae of previous diseases, the elderly,
i.e., persons older than 75 years, represent a distinct population. They differ from
younger adults in terms of pharmacokinetics and pharmacodynamics (Greenblatt et
E-mail address: georgenhaus@t-online.de (J. Zeeh).
0167-4943/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 1 6 7 - 4 9 4 3 ( 0 1 ) 0 0 0 9 0 - 5

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J. Zeeh / Arch. Gerontol. Geriatr. 32 (2001) 255–263

al., 1986; Platt, 1986; Montamat et al., 1989) and these differences can be mainly
attributed to decreased liver and renal function, reduced cardiac output, impaired
pulmonary function and to reductions in body weight, muscle mass and changes in
body composition (Wynne et al., 1989; Durnas et al., 1990; Lindeman, 1992).
Furthermore, the possibility of drug interactions has to be taken into account as
elderly patients frequently receive extensive drug treatment for coexistent illnesses.
The incidence of many diseases increases with age and multimorbidity occurs
most often in the elderly and oldest old. Therefore, prescribing for those frail
elderly subjects is a major challenge for the medical practitioner. On the one hand,
the frail elderly may require, and may potentially benefit from several medications.
On the other hand, such polypharmacotherapy may also be harmful, as untoward
drug reactions are recognized causes of morbidity in old age. Hurwitz (1969) in a
pioneering survey of more than 1200 elderly patients admitted to an acute care
hospital, found the incidence of adverse drug reactions more than tripled beyond
the age of 70 years. This tendency may even be more pronounced in frail nursing
home patients. It has been shown that 11.6% of all patients beyond the age of 65
years admitted to community hospitals had been admitted because of drug-induced
conditions (Colt and Shapiro, 1989). In part, this is due to the fact that with
declining renal and hepatic function and with a smaller body mass, ‘usual’ adult
doses may represent relative overdoses for many elderly. For renally excreted drugs
this may be overcome by meticulous assessment of actual renal function, whereas at
present no routine tests of hepatic drug metabolizing capacity are available.
Therefore, therapeutic drug monitoring may contribute to avoid dose related drug
toxicity. Whereas anaphylactic and allergic drug reactions seem to occur independently from age, the frequency of drug– drug interactions and adverse drug
reactions due to unexpectedly high blood concentrations of the drug are increasing
in elderly patients. Therefore, the elderly not only have an increase in adverse drug
reactions associated with abnormally high blood levels of many drugs, but also
have more adverse effects at therapeutic blood levels. Several mechanisms may
account for that (Table 1).
For most side effects encountered in the elderly, remarkably little data is
available to support the commonly held view that the incidence of adverse drug
reactions increases with patient age as an independent risk factor (Nolan and
O’Malley, 1988). After taking into account the doses administered and the duration
of therapy, a positive correlation between increasing patient age and the occurrence
of side effects may no longer be observed (Gurwitz and Avorn, 1991). This
underscores the importance of careful and sensible prescribing for the elderly.
However, comorbidity and limited reserve capacities of many organ systems often
make the elderly more vulnerable for untoward side effects of drugs (Table 2).

2. Morphological changes of the aging liver
Macroscopically the liver is described as undergoing brown atrophy with old age.
In autopsy studies, aging was found to be associated with a 24% reduction in liver

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257

Table 1
Age-related changes and potentially resulting problems in the pharmacotherapy of elderly persons and
their estimated relative importance
Confounding factors

Relative
importance

Remarks and examples

Compliance problems in old patients
taking many drugs

Very important

Errors sharply increase when more
than four drugs are being prescribed at
a time

Altered drug absorption from the aging
gastrointestinal tract
Altered protein binding due to altered
plasma protein pattern
Altered volume of distribution due to
changing body composition and body
mass
Impaired liver function
Impaired renal excretion

Unimportant

Altered end organ susceptibility to drug
effects
Failure of compensatory mechanisms

Very important

Possibly
important
Important

Important
Very important

Very important

Increases glomerular excretion and
tissue drug concentration
Diazepam has a markedly prolonged
half-life in the elderly due to a
increased volume of distribution
Glomerular filtration decreases with
age
The risk of falls is increased in subjects
taking sedative drugs
Arthritis and impaired postural control
may aggravate the risk of falls after a
variety of psychotropic drugs

weight in males and a 18% reduction in females. This trend has been confirmed with
different techniques (Table 3) and in general, the reduction of liver size is noted to
be in the order of 25– 35% (Le Couteur and McLean, 1998). Apart from this decline
in liver volume, there are few if any age-associated changes in liver structure
correlating with perturbations in hepatic function. Physiological and morphological
studies suggest that, compared to other organs, the liver seems to age fairly well.
Table 2
Characteristic side effects of drugs frequently used in the elderly
Target organ system, effect

Offended drugs

Reference

Metabolic system,
hypokalaemia
Genitourinary system, urinary
retention
Gastrointestinal system, ulcer
bleed
Cardiovascular system,
postural hypotension
Nervous system, confusion

Diuretics

Levy and Lye (1987)

Anticholinergics, benzodiazepines

Iber et al. (1994)

Nonsteroidal anti-inflammatory drugs

Iber et al. (1994)

Diuretics, antihypertensive drugs

Sabanathan et al. (1987)

Anticholinergics, psychotropic drugs,
H2-blockers
Psychotropic drugs

Iber et al. (1994)

Locomotor system, falls and
fractures

Ray et al. (2000),
Ray et al., (1987)

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258

Table 3
Liver volume and age (Wynne et al., 1989; Zeeh and Platt, 1990; Iber et al., 1994; Le Couteur and
McLean, 1998)
Technique

n

Autopsy

1582

Ultrasound
Ultrasound
Ultrasound
Ultrasound

Age range
(years)

26
50
65
32

20–80
25–80
B50–B80
24–91
B55–\70

Decline relative (%) Decline absolute
(ml)

Year of
publication

24% (male), 18%
(female)
24%
32%
37%
20

1933

–
1303 “ 990
–
1474 “ 934
1446 “1157

1978
1988
1989
1994

Routine liver function tests do not show age-associated changes. Perhaps the
most compelling evidence for the maintenance of hepatic function into advanced age comes from clinical practice, wherein livers from elderly subjects,
including one donor aged 86 years, have been transplanted successfully (Schmucker,
1998).

Fig. 1. Liver perfusion as determined by extrarenal sorbitol clearance (ER-S-Cl; Zeeh et al., 1988) in 86
subjects aged 40 –95 years without liver disease (own data, black columns denote mean values, topped
grey columns indicate +SD).

J. Zeeh / Arch. Gerontol. Geriatr. 32 (2001) 255–263

259

3. Hepatic blood flow
Old age is unambiguously associated with a reduction in hepatic blood flow of
about 35 –40% (Fig. 1). This has been documented using a variety of technical
methods including dye dilution and indicator clearance, indicator distribution and
Doppler ultrasound (Wynne et al., 1989; Woodhouse and Wynne, 1992; Zoli et al.,
1999). This decrease is probably due to a diminished splanchnic blood flow which
reduced input of blood into the portal vein. Bile flow and bile salt formation are
reduced by about 50% reflecting, at least in part, impairment of energy dependent
and microtubule-dependent transport processes (Le Couteur and McLean, 1998).

4. Principles of hepatic drug clearance
By examining the characteristics and behaviour of some drugs and their metabolites it is possible to infer certain characteristics about the aging liver. Phase I of
hepatic drug metabolism leads to structural alteration of the metabolized drug by
oxidation, reduction and hydrolysis and depends on the amount and activity of the
specific microsomal enzymes. Thereafter, phase II metabolism leads to conjugation
with chemical ligands such as glucuronide, sulphate, acetate or glutathione, again
dependent upon the activity of specific cytosolic enzymes.
Hepatic clearance (Clhep) is defined by the equation
Clhep =Q × E

(1)

where Q is the hepatic blood flow and E is the hepatic extraction fraction, the
fractional removal of the given drug by the liver. Some substances eliminated by the
liver have an extraction rate that approximates unity. This type of metabolism is
called flow limited, because hepatic clearance will be almost equal to hepatic blood
flow. Using this principle, the clearance of highly extracted like indocyanine green
and sorbitol have been used to estimate hepatic blood flow (Zeeh et al., 1988). On
the other hand, the clearance of drugs with a low extraction fraction is not
influenced by blood flow. The metabolism of these drugs is influenced by intrinsic
clearance (a term that describes total enzyme activity and liver mass) and/or protein
binding and is termed capacity-limited (Table 4). The clearances of those compounds, such as antipyrine and galactose, have been used to describe liver size. The
relationship between hepatic clearance (Clhep) and parameters such as hepatic flow
(Q), intrinsic clearance (Clint) and the unbound fraction ( fu) has been described by
various models. The simplest model is the venous equilibrium model, which
assumes complete mixing of substrates within the liver and can be summarized as
follows:
Clhep =

Q× fu ×Clint
.
Q +( fu ×Clint)

(2)

Phase I and phase II are terms used to describe the major enzymatic pathways in
the liver, metabolizing drugs and other xenobiotics. Both pathways tend to increase

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Table 4
Examples of high- and low-extraction drugs (Durnas et al., 1990; Zeeh and Platt, 1993)
High-extraction drugs

Low-extraction drugs

Amitryptiline
Bromocriptine
Clomethiazole
Diltiazem
Dothiepin
Ergotamine
Isosorbitdinitrate
Labetalol
Metoprolol
Nifedipine
Propranolol
Triamterene
Verapamil

Antipyrine
Carbamazepine
Chlordiazepoxide
Caffeine
Diazepam
Flunitrazepam
Indomethazine
Oxazepam
Phenprocoumone
Phenytoin
Prednisolone
Theophylline

the water solubility of compounds and facilitate renal excretion. Phase I reactions
alter the structure of a compound by oxidation, reduction, hydrolysis and demethylation and are performed mostly by the cytochrome-P (CYP) system of enzymes
within the endoplasmic reticulum. Phase II reactions involve the addition of polar
chemical groups such as glucuronide, sulphate, glycine, glutathione and acetate.
These reactions occur mainly in the cytosol. Recent studies indicate that the activity
of phase I enzymes is more dependent on the delivery of oxygen than that of phase
II enzymes. Many drugs, including some tricyclic antidepressants and benzodiazepines, are metabolized extensively by both pathways prior to excretion by the
urine or bile. Drug elimination can also be influenced by many other factors such
as drug absorption, extra-hepatic metabolism, tissue distribution, protein binding
and renal excretion. Therefore, in order to assess the effects of age on the liver, it
is preferable to examine drugs that are not influenced by renal excretion or other
routes of elimination and where absorption is not affected by age. It should be
noted that these traditional approaches to the understanding of hepatic drug
metabolism make the assumptions that there are no limitations on the supply of
oxygen and/or other cofactors and that other substrates including drugs have
unimpeded access to enzymes. It also assumes that no changes in physicochemical
parameters such as intracellular pH and osmolality will impact on enzyme function.

5. Potential limitations of drug studies on aging
The aging process is quite different from person to person, so that among a
group of 70-year-old persons, there are a few who appear much younger, those who
appear that age and some who appear older. This heterogeneity of an aging cohort
of normal individuals is also evident in physiological terms, which affects the
metabolism, excretion and toxicity of drugs (Iber et al., 1994). Furthermore,

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261

subclinical diseases in apparently normal persons, the parallel intake of drugs both
over-the-counter and prescribed ones, smoking habits, nutritional differences and
other factors may be superimposed to the aging process. In patients, the effects of
disease and of comedications need to be considered which makes things even more
complex. At all ages there is wide genetic variability or polymorphism in the rates
of drug clearance, which is commonly 2–5-fold and occasionally up to 30-fold and
clearly persists even in old age. Examples are the acetylator status and differences
within the family of cytochrome P-450 isoenzymes. Furthermore, differences in the
clearance or hepatic metabolism of one stereoisomer compared with the other have
been found for metoprolol, verapamil, salbutamol and felodipine. All these factors
provide ‘noise’ and contribute to the wide variability in drug clearance studies
performed to detect the effects of aging.

6. Findings, considerations and hypotheses
In an attempt to reduce the incidence of adverse drug reactions, much research
into the effect of age on drug metabolism has been done. Despite significant efforts,
the effect of age on hepatic drug metabolism continues to be a controversial issue.
Well known changes in the clearance of drugs that undergo hepatic metabolism
may be attributed to age associated alterations in hepatic enzyme activity and, more
importantly, to reduced liver size and hepatic blood flow.
The ability of the aging liver to metabolize drugs does not decline in a similar
way and extent for all pharmacological agents. Several changes in hepatic function
and structure have been noted in the elderly, and many of them seem to be of
limited relevance. Two of them, however, are of major importance. These are an
absolute and relative to body-weight decrease in liver size and mass and a reduced
regional blood flow to the organ (Hammerlein et al., 1998). The most frequent
¨
changes involve the mixed-function oxidase system of phase I oxidation and
reduction, with little or no change in the processes of phase II conjugation.
However, there have also been reports where the activities and amounts of liver
microsomal monooxygenases remained unaltered with increasing age (Schmucker et
al., 1990). The reasons for these discrepancies between clinically observed decline in
drug elimination and unchanged metabolic activity in vitro are probably attributable to interindividual variability, and to the difficulty of getting representative liver samples from healthy elderly subjects. A review of age-related change in
drug clearance 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 further explanations. By analogy with our understanding of drug
metabolism in liver disease, it may be assumed, that a hepatocyte diffusion barrier
to oxygen develops with increasing age. This provides a plausible explanation for
the paradox and has some experimental support (Le Couteur and McLean, 1998).

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7. Consequences for clinical practice
More than ten years after our previous review of the topic (Zeeh and Platt, 1990)
and after an other decade of research into the consequences of aging on drug
treatment of the elderly patient, the old and well known aphorism ‘start lower —
go slower’ is valid more than ever. Not only renally excreted drugs but also
substances metabolized and excreted by the liver should be used in a starting dose
which is 30– 40% smaller than the average dose used in middle-aged adults. The
steps by which this dose is increased, as clinically indicated should also be smaller
and the patient be closely monitored for the occurrence of drug toxicity. As
compliance problems may be regarded as major problem in the elderly, and intake
errors rise sharply with the number of drugs prescribed, the most hazardous drug
in the elderly may be ‘the fourth’, which is added to a treatment regimen of three
other drugs (Haefeli, 1995).

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