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Age-Related Changes in Hepatic Function: An Update on Implications for

Drug Therapy

Article  in  Drugs & Aging · December 2015

DOI: 10.1007/s40266-015-0318-1

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Drugs Aging (2015) 32:999–1008
DOI 10.1007/s40266-015-0318-1

REVIEW ARTICLE

Age-Related Changes in Hepatic Function: An Update

on Implications for Drug Therapy
Joseph L. Tan1 • Jacques G. Eastment1 • Arjun Poudel2 • Ruth E. Hubbard1

Published online: 7 November 2015

 Springer International Publishing Switzerland 2015

Abstract The accumulation of deficits with increasing capacity-limited. By summarising the effect of age-related
age results in a decline in the functional capacity of mul- changes in hepatic function on medications commonly
tiple organs and systems. These changes can have a sig- used in older people, we aim to provide a guide that will
nificant influence on the pharmacokinetics and have high clinical utility for practising geriatricians.
pharmacodynamics of prescribed drugs. Although alter-
ations in body composition and worsening renal clearance
are important considerations, for most drugs the liver has
Key Points
the greatest effect on metabolism. Age-related change in
hepatic function thereby causes much of the variability in
Age-related change in hepatic function causes much
older people’s responses to medication. In this review, we
of the variability in older people’s responses to
propose that a decline in the ability of the liver to inactivate
medication.
toxins may contribute to a proinflammatory state in which
frailty can develop. Since inflammation also downregulates In the absence of randomised controlled trials
drug metabolism, medication prescribed to frail older supporting titration of doses in older people, an
people in accordance with disease-specific guidelines may appreciation of the fundamental pharmacokinetic
undergo reduced systemic clearance, leading to adverse changes related to hepatic drug clearance and protein
drug reactions, further functional decline and increasing binding can guide clinicians in their decision making
polypharmacy, exacerbating rather than ameliorating concerning dose adjustment.
frailty status. We also describe how increasing chrono- A decline in the ability of the liver to inactivate
logical age and frailty status impact liver size, blood flow toxins may contribute to a proinflammatory state in
and protein binding and enzymes of drug metabolism. This which frailty can develop.
is used to contextualise our discussion of appropriate pre-
scribing practices. For example, while the general axiom of
‘start low, go slow’ should underpin the initiation of
medication (titrating to a defined therapeutic goal), it is
important to consider whether drug clearance is flow or
1 Introduction

& Ruth E. Hubbard Since the 1970s, increases in average life expectancy have
r.hubbard1@uq.edu.au been predominantly driven by reduced mortality among
1 older people [1]. While cancer, chronic obstructive pul-
Centre for Research in Geriatric Medicine, School of
Medicine, The University of Queensland, Princess Alexandra monary disease and pneumonia (including influenza) are
Hospital, Woolloongabba, Brisbane, QLD 4102, Australia the leading causes of death for persons aged over 65 years
2
School of Pharmacy, The University of Queensland, of age [2], the primary reason for this mortality reduction is
Brisbane, QLD, Australia a decrease in atherosclerotic-related illness, particularly
1000
ischemic heart disease and stroke [1]. Pharmacotherapy, in
addition to lifestyle modification, is therefore likely serving
a critical beneficial role; however, there is increasing
concern that medications can cause significant harm to
older people, particularly when multiple drugs are pre-
scribed [3]. When prescribing a medication, it is essential
to include an understanding of the patient’s own goals of
care, the burden of medication and, importantly, the risks
of harm for each drug against its current or future benefit.
Such harm can only be estimated through understanding
the interplay between intrinsic factors (pharmacokinetics
and pharmacodynamics) and extrinsic factors (prescribing
and medication management) [4]. A range of clinical and
pathological factors and age-related changes in organ
function and homeostatic control influence the pharma-
cokinetics and pharmacodynamics of a drug [5]. While
major alterations in body composition and a decline in
renal function are contributing factors, the change in liver
function with ageing has the greatest impact on drug
clearance and variability in response to most medicines [6].
This review will describe how increasing chronological
age impacts liver size and blood flow, enzymes of drug
metabolism, and detoxification/inflammatory responses.
This will contextualise our discussion of the clinical
implications of age-related changes in hepatic function and
inform appropriate prescribing practices for older people.
2 Literature Search
A literature search was performed to identify previous
studies investigating the effects of ageing on hepatic
metabolism of medications. The search strategy is detailed
in ‘‘Appendix’’, and publications were identified in
EMBASE and PubMed.
Thirty-three articles pertaining to humans were initially
identified using the described search terms on Pubmed,
with 8 articles being manually removed after being deemed
to be inappropriate inclusions. Of the remaining 25 articles,
all were reviews with no results of human-based ran-
domised controlled trials or cohort studies analysing the
effects of aging on the hepatic metabolism of xenobiotics.
EMBASE searches (see ‘‘Appendix’’) identified 139
relevant articles. Stratifying these results by study type, we
found that there were 35 clinical trials or controlled studies,
7 major clinical studies, and 8 meta-analyses. Six articles
classified as ‘clinical trial’ or ‘controlled study’ were
manually removed. Phenytoin was the most studied med-
ication (30/139 articles), followed by nonsteroidal anti-in-
flammatory drugs (27/139 articles) and carbamazepine
(25/139 articles).
The most clinically relevant identified papers were uti-
lised for this manuscript.
J. L. Tan et al.
3 Age-Related Changes in Hepatic Size, Blood
Flow Clearance and Protein Binding
Hepatic drug clearance can be either flow-limited or
capacity-limited, and is significantly altered in aging due to
changes in liver size and blood flow. Protein binding,
particularly involving albumin, also contributes to a drug’s
total clearance [7].
3.1 Age-Related Changes to Hepatic Size and Blood
flow
Age-related change in the liver sees a decline in organ volume
that ranges between 20 and 40 % across the adult lifespan [8].
Studies suggest that reduced liver volume is associated with
age-related decline in drug clearance. More significant is the
age-related decline in hepatic blood flow, and therefore sub-
strate delivery to the liver parenchyma, which is cited to
reduce between 40 and 60 % in the elderly [6, 7, 9, 10]. This
occurs due to the accumulation of leukocytes in the sinusoids,
narrowing of sinusoidal lumens and dysfunction of the liver
sinusoidal endothelial cells [11]. These changes in liver
sinusoidal endothelial cells may further alter drug transfer
from the blood to hepatocytes [6]. As hepatic clearance
depends upon substrate delivery to the hepatocytes and the
inherent metabolic capacity of the hepatocytes, the conse-
quent reductions in blood flow and drug transfer leads to the
fall in clearance of many drugs whose pharmacokinetics are
found to be altered with increasing age, especially those
dependent on flow-limited clearance [9].
3.2 Flow- vs. Capacity-Limited Hepatic Clearance
Hepatic drug clearance can be either flow-limited (high hep-
atic extraction or clearance) or capacity-limited (low hepatic
extraction or clearance). As a result of decreased hepatic blood
flow, flow-limited drug clearance has been shown to be con-
sistently impaired in aging. However, changes in capacity-
limited drug clearance have been more difficult to demon-
strate and are influenced by a drug’s affinity for protein
binding [7]. Le Couteur and McLean determined that capac-
ity-limited drugs that had reduced clearance in elderly people
were predominantly those with low protein binding. In con-
trast, clearance of capacity-limited drugs that were highly
protein bound, such as valproic acid, warfarin, phenytoin and
diazepam, were largely unchanged [10].
3.3 Age-Related Changes to Protein Binding
Lower protein (particularly albumin) concentrations in
aging reduce the degree of drug-protein binding overall [7].
Because a drug’s steady-state free concentration in plasma
Age-Related Changes in Hepatic Function
is itself determined by hepatic intrinsic clearance, reduced
protein binding will result in a higher free fraction of drug
but will not alter absolute free drug levels unless changes
are present that also affect dosage rate or intrinsic clear-
ance (such as aging). In a drug that is highly protein bound,
a reduction in protein binding results in a lower total
(bound and unbound) drug concentration [7].
Although categorisation of drugs based on hepatic
metabolism and plasma protein binding helps understand
the effect of liver disease on drug pharmacokinetics, pre-
dicting responses to individual medications can still be
difficult. In the absence of randomised controlled trials
supporting titration of doses in older people, an apprecia-
tion of the fundamental pharmacokinetic changes related to
hepatic drug clearance and protein binding will be helpful
to guide clinicians in their decision making concerning
dose adjustment [7, 12].
4 Age-Related Changes in Enzymes of Drug
Metabolism
4.1 Phase I Enzymes
Phase I metabolism describes the hepatic enzyme-mediated
process by which water-insoluble drugs and toxins are
converted into water-soluble (polar) molecules, enhancing
excretion from the body. The major hepatic catalysts for
these reactions are the cytochromes P450 (CYP), a super-
family of oxidative enzymes [13]. The most commonly
prescribed drugs are metabolised by enzymes belonging to
one of three subgroups of CYPs—CYP1, CYP2 and CYP3
[14].
Literature surrounding the impact of ageing on phase I
metabolism remains mixed [8]. Studies analysing the cel-
lular activity of CYP catalysts have concluded that there is
no significant difference in enzymatic activity observed in
young versus old liver cells; [8, 15] however, one extensive
review concluded that xenobiotics metabolised by the
CYP3A family undergo reduced hepatic clearance in older
persons [16]. This perhaps suggests that the impact of
ageing on phase I drug metabolism may be compound-
specific and requires further elucidation. Another expla-
nation for this could be that frailty, not age, is a major
determinant of phase I enzymatic dysfunction and adverse
drug events in the elderly. A study that used erythromycin
breath test as a marker of CYP3A4 metabolic activity
found that the oldest old ([80 years) maintain the ability to
metabolise CYP3A4 substrates and that frail older people
do not generally show reduced drug clearance [17]. How-
ever, this finding was complicated when erythromycin was
1001
reported as an imperfect probe for CYP3A4 activity as it
also acted as a substrate for the drug efflux transporter,
hepatic P-glycoprotein. A study that compared the plasma
esterase activity in fit and frail older patients found normal
plasma esterase activity in the healthy volunteers which fell
significantly with increasing frailty [18]. Le Couteur and
McLean have previously suggested that the findings of
in vitro studies (i.e. that there is no age-related change in
phase I metabolism) and in vivo studies (i.e. there is
reduced clearance of phase I substrates in older persons)
could be explained by structural changes in aged liver cells
that impede oxygen diffusion and hence reduce hepatic
capacity for phase I oxidation [10].
4.2 Phase II Enzymes
Hepatic phase II reactions describe the enzymatic addition
of hydrophilic groups to xenobiotics (or their derivative) to
enhance excretion. Common phase II enzymes include
uridine diphosphate (UDP)-glucoronyl transferase and
glutathione S-transferase. Common antiepileptic drugs
which are metabolised via phase II enzymes and that
demonstrate an altered pharmacokinetic profile in the
elderly include lamotrigine [19] and oxazepam [20].
Phase II reactions have previously been thought to be
relatively unaffected by aging; however, inadequate con-
sideration of protein binding may have confounded this
conclusion, with high-level evidence for reduced phase II
metabolism of paracetamol, valproic acid and naproxen,
and low- to medium-level evidence for reduced phase II
metabolism of temazepam and lorazepam [6, 7].
Importantly, it again appears that frailty, rather than
chronological age, may impact phase II metabolism [21].
Studies on paracetamol and metoclopramide revealed that
paracetamol clearance was reduced in both fit and frail
older people compared with younger controls but, when
corrected for liver size, the glucuronidation of paracetamol
was markedly lower in frail older people compared with
their fitter peers [22]. Similarly, clearance of metoclo-
pramide by sulphation was similar in young controls and fit
older people, but significantly reduced in those who were
frail [23].
4.3 Phase III Enzymes
The phase III metabolism of xenobiotics is characterised by
their transportation from hepatocytes into the biliary sys-
tem for excretion. This is mediated by a number of trans-
port proteins [24]. One study using rat liver models,
demonstrated a positive correlation between aging and
expression of the P-glycoprotein transporter [25].
1002
5 Age-Related Changes in Detoxification
and Inflammatory Responses
In addition to its role in drug metabolism, the liver has a
critical function to neutralise and eliminate toxins [26]. One
such toxin is the gut microflora-derived lipopolysaccharide
(LPS), which has been shown to induce chronic hepatic
inflammation. The liver plays a critical role in LPS inactiva-
tion by direct detoxification by hepatocytes and through the
production of anti-inflammatory cytokines by Kupffer cells.
Murine models have demonstrated that LPS challenges in
older mice produce higher levels of cytokines compared with
younger animals [27]. Aged rat livers are also more likely to
undergo endotoxin-induced inflammatory changes, such as
hepatic lipid accumulation, relative to younger rat livers [28].
Shedlofsky et al. performed a small study in which healthy
human volunteers received small doses of LPS with subse-
quent assessment of oral drug clearances (antipyrine, hexo-
barbital and theophylline). Subjects developed a physiological
inflammatory response that correlated to reductions in drug
clearances in a dose-dependent manner [29].
Interestingly, inflammation is closely linked to frailty
[30, 31]. While it has been argued that inflammation is an
epiphenomenon, merely a marker of another key patho-
physiological process, such as oxidative stress [31], there is
a growing body of evidence suggesting inflammation has a
causal role in frailty development [32–34].
An age-related decline in the ability of the liver to inacti-
vate toxins may contribute to the proinflammatory state in
which frailty can develop and then progress. Inflammation,
septic or aseptic, also downregulates drug metabolism. It
generally results in decreased expression of messenger RNA
and, consequently, protein synthesis of CYPs [35, 36]. Simi-
larly, there is a weak but significant negative correlation
between inflammatory cytokines and esterase activity [18]. A
cycle can be conceptualised in which age-related inflamma-
tion leads to chronic disease and frailty, yet the medication
prescribed in accordance with disease-specific guidelines
undergoes reduced systemic clearance. Inflammation and
steatohepatitis have been shown to alter hepatic drug meta-
bolism and hence potentially contribute towards the higher
incidence of adverse drug reactions in older persons [37, 38].
The resulting adverse drug effects could trigger further func-
tional decline and increasing, inappropriate polypharmacy,
exacerbating rather than ameliorating frailty status.
6 Clinical Implications
Since changes in hepatic metabolism affect both bioavail-
ability, through reduced first-pass effect, and hepatic clear-
ance, they represent major pharmacokinetic factors that need
J. L. Tan et al.
to be considered when prescribing [39]. Guidelines have
been developed for the adjustment of medication in people
with known hepatic impairments; however, these tend to
categorise patients based on the Child–Pugh classification
system which incorporates five variables to assess the
severity of liver disease: serum bilirubin, serum albumin,
prothrombin time, the presence of encephalopathy, and the
presence of ascites. Disease severity is then classified as
mild, moderate or severe [12]. These classification schemes
are useful to guide clinicians regarding dose adjustment for
patients with overt liver disease, but are not targeted at older
patients with more subtle multisystem impairments.
In older people, the general axiom of ‘start low, go slow’
should underpin the initiation of medication in non-emer-
gencies. However, while selecting a starting dose, it is
important to consider whether the drug is a prodrug, and
whether it has active or toxic metabolites. For example, sim-
vastatin is a prodrug that is reliant on conversion to its active
metabolites by phase I metabolism, and this process is reduced
in older people. Theoretically, therefore, for therapeutic
effects to be maintained, older people may be at increased risk
of toxic effects from the accumulated prodrug [39].
For drugs with capacity-limited metabolism (low hep-
atic extraction) and high plasma protein binding, dose
adjustment should be based on unbound/free blood con-
centrations, even though total blood/plasma concentrations
are within the normal range [12]. For capacity-limited
drugs with low plasma protein binding, total clearance will
be reduced due to reduced hepatic intrinsic clearance, and
hence dose adjustment should be aimed at maintaining
normal total plasma concentrations [7, 12].
The clearance of flow-limited drugs (such as pethidine,
morphine, propranolol and verapamil) is reduced more sig-
nificantly than that of capacity-limited drugs (such as dia-
zepam, phenytoin, warfarin and salicylic acid) [39]. The
metabolism of flow-limited drugs is reduced by approxi-
mately 40–60 %, consistent with the reduction in blood flow
in older people. There is evidence to show that phase I, as
well as (once protein binding is taken into account) phase II
drug metabolism is reduced in aging [6, 7, 10, 39, 40].
Many older people are now exposed to polypharmacy
and hyper-polypharmacy, with a mean of 7.6 different
medications prescribed on discharge from hospital [41].
The potential for drug–drug interactions to affect hepatic
drug clearance should also be taken into account.
Many predictable effects occur through the induction
(multiple substrates competing for enzyme catalytic sites
on a single CYP450 enzyme) or inhibition (substrate
exposure causes easing of regulatory process to increase
enzyme levels) of the CYP pathways of hepatic metabo-
lism. More recently, drug–drug interactions have also been
recognised in phase III metabolism [39, 42, 43].
Table 1 Effect of age on hepatic metabolism and implications for prescribing
Drug class Impact of hepatic changes on metabolism Implications for clinical use Flow (F)- vs. Capacity
(C)-limited clearance
(where known) [44]

Antiplatelet agents
Direct-acting agents Direct-acting antiplatelet agents such as cangrelor, ticagrelor and None
Prodrugs cilostazol have reversible effects and do not require hepatic
metabolism for achieving pharmacodynamic activity. However,
for prodrugs, such as clopidogrel, that need hepatic
biotransformation into its active metabolite, approximately 85 %
is hydrolysed prehepatically by esterases into an inactive
compound; thus, only 15 % is available for hepatic metabolism
Age-Related Changes in Hepatic Function

[45]
Antihypertensives
CCBs CCBs are substrates of CYP3A4. All are significantly bound to Start with low dose and titrate according to response F
• Dihydropyridine plasma protein [46]
(amlodipine, felodipine,
lercanidipine,
nifedipine)
• Non-dihydropyridine
(diltiazem, verapamil)
Thiazide diuretics Thiazide diuretics and the majority of thiazide-like diuretics are None NA
essentially unchanged and known not to undergo metabolism [46]
ACE inhibitors With the exception of lisinopril and captopril, which have Start with low dose and titrate according to response
significant oral bioavailability, most ACE inhibitors are prodrugs
that require hepatic esterolysis to produce active diacid
metabolites, which are then excreted by the kidneys [46]
Antiarrhythmics
b-Blockers Metoprolol, propranolol, bisoprolol and carvedilol are metabolised Start with low dose and titrate according to response. Whilst the F
by CYP2D6 predominantly and in varying degrees by other choice of atenolol may offer relatively consistent systemic
CYP450 enzymes, including CYP3A4 [14]. Atenolol undergoes bioavailability compared with other b-blockers, renal function in
very little hepatic metabolism (\10 %) and is predominantly the elderly must be considered
excreted renally
Digoxin Although undergoing some metabolism by CYP3A4, digoxin is not Since measured drug levels reflect total drug in serum (bound and NA
strongly influenced by first-pass metabolism, with unbound),frail older people taking digoxin are more prone to
pharmacokinetics largely driven by P-glycoprotein, which is toxicity even with ‘normal’ drug levels
located on enterocytes and renal proximal tubules [47]
As an acidic drug, digoxin is extensively bound to albumin, which
declines in frail older people. More unbound drug may be
available for passive diffusion to extravascular or tissue sites
where the pharmacologic effects of the drug occur [48]
1003
Table 1 continued
1004

Drug class Impact of hepatic changes on metabolism Implications for clinical use Flow (F)- vs. Capacity
(C)-limited clearance
(where known) [44]

Analgesics
Opioids In addition to glucuronidation, opiates undergo metabolism by Transdermal patches (available for fentanyl and buprenorphine) F
CYP2D6 and CYP3A4, with fentanyl undergoing rapid bypass first-pass metabolism and may provide more
metabolism by CYP3A4 [49] predictable pharmacokinetics in more frail patients, but consider
variable uptake due to changes in skin structure and cutaneous
blood flow
Paracetamol Risk factors for hepatotoxicity include malnutrition and chronic Reduce dosing in patients with risk factors for paracetamol-induced C
alcohol abuse (both deplete glutathione, with alcohol further hepatotoxicity
inducing CYP2E1), use of CYP450 inducers and chronic liver
disease [6]
Antidepressants
SSRIs The SSRIs, like the tricyclics, are similarly metabolised by Careful dose titration and vigilance for potentiating effects of other F
CYP2D6, and are highly protein bound; however, these also drugs
inhibit other CYP450 isoforms, including CYP2D6 itself,
CYP3A4, CYP2C19 and CYP1A2
Tricyclics The tricyclic group of antidepressants are metabolised primarily by Start with low dose and titrate according to response F
CYP2D, with amitriptyline and imipramine also substrates of
other isoforms CYP3A4, CYP2C19 and CYP2C9. Highly protein
bound
Duloxetine Substrates of CYP2D6 F
Vanlafaxine, F
mirtazepine
Benzodiazepines
Diazepam The oxidative metabolism of diazepam is mediated by CYP3A and Due to a longer half-life of metabolites, the dosing interval of C
CYP2C19 isoenzymes to hydroxydiazepam (temazepam) and diazepam may be increased
nordiazepam (t‘ approximately 96 h)
Oxazepam, lorazepam, Benzodiazepines such as oxazepam, lorazepam and temazepam are Cautious use in the short-term. Vigilance recommended for C
temazepam not affected by age-related decrease in hepatic clearance because rebound symptoms in between regular doses
they are metabolised by glucuronidation, a process not affected by
aging [50, 51]
Statins Metabolised by CYP3A4 and CYP2C9. The effect of ageing on the None F
risk of hepatic damage with statins is not known [52]
PPIs Anti-ulcer agents undergo extensive hepatic biotransformation None C
before elimination. The CYP450 isoenzymes involved in anti-
ulcer drug metabolism undergo significant genetic
polymorphisms which may substantially increase plasma levels of
omeprazole, lansoprazole and pantoprazole, but not those of
rabeprazole [53, 54]
Antipsychotics
Haloperidol, risperidone Substrates of CYP2D6 Start with low dose and titrate according to response F
J. L. Tan et al.
Table 1 continued
Drug class Impact of hepatic changes on metabolism Implications for clinical use Flow (F)- vs. Capacity
(C)-limited clearance
(where known) [44]

Quetiapine Predominantly substrate of CYP3A4 None F

Olanzepine In addition to conjugation, metabolised by oxidative pathways Start with low dose and titrate according to response F
CYP1A2 and CYP2D6
Oral hypoglycemics
Metformin Does not undergo hepatic metabolism None
Sulphonylureas Substrates of CYP2C9, CYP2C19. Plasma protein binding of Start with low dose and titrate according to response C
gliclazide approximates 95 %
Age-Related Changes in Hepatic Function

Anticonvulsants
Valproic acid Protein binding approximately 90 %, 60 % of which is albumin. Where albumin is decreased, free drug concentrations may rise out C
Metabolised predominantly by phase II reactions of proportion to any increase in dose
(glucuronidation), with the remainder via phase I oxidation
pathways
Phenytoin Protein binding approximately 90 %. Substrate of CYP2C9, C
CYP2C19
Carbamazepine Protein binding 70–80 %. Substrate of CYP3A4 C
Antiemetics
Metoclopramide Extensively metabolised into sulphate (approximately half) and a Strong recommendation to avoid metoclopramide in older people
small amount to the glucuronide metabolite. Clearance seems to (unless for gastroparesis) due to extrapyramidal effects [55]
be reduced in frail older people due to impairment of conjugation
pathways including sulphation [23]
Anticoagulants
Novel anticoagulants Renal excretion of apixaban accounts for approximately 27 % of Dosing based on a calculated GFR rather than an estimated GFR is
(including dabigatran, total clearance. Plasma protein binding approximately 87 %. recommended
apixaban and Rivaroxiban undergoes approximately 66 % metabolic degradation
rivaroxaban) via CYP3A4 and CYP2. The remaining 34 % undergoes direct
renal excretion as unchanged active substance. Plasma protein
binding approximately 92–95 %
Dabigatran is eliminated primarily in the unchanged form in the
urine
Warfarin Extensive metabolism by CYP450 (2C9, 2C19, 2C8, 2C18, 1A2 As patient age increases, less warfarin is required to produce a C
and 3A4) to inactive hydroxylated metabolites (predominant therapeutic level of anticoagulation. Consider interactions with
route) and by reductases to reduced metabolites (warfarin other drugs (inhibition/induction)
alcohols)
Approximately 99 % protein-bound
Data taken from MIMs online [56] unless otherwise cited
ACE angiotensin-converting enzyme, CCBs calcium channel blockers, CYP cytochrome P450, PPIs proton pump inhibitors, SSRI serotonin-specific reuptake inhibitors, GFR glomerular
filtration rate, NA not applicable
1005
1006 J. L. Tan et al.

The implications of age-related hepatic changes on the
prescribing of commonly used medications are summarised
in Table 1. The most prevalent drug classes prescribed to
older inpatients have been included [41], but we
acknowledge that the list is not exhaustive.
Optimal pharmacotherapy warrants an understanding of
goals of care and risks of harm, as well as evaluating current or
future benefit. Although there are established interrelationships
between aging processes, comorbidities and pharmacokinetics,
safety and efficacy data in frail older people are limited.

8 Future Research
7 Conclusions
Further studies should evaluate the complex interplay
Age and frailty status are both likely to affect the phar-
between aging and subacute inflammation. Within the
macokinetics and pharmacodynamics of medications, and
elderly population itself, comparisons between frail and
hence should influence prescribing. An understanding of
non-frail patients with regard to protein binding and
impaired hepatic metabolism of drugs in older people can
inflammation may shed further light on pharmacokinetics
guide the clinician in titrating doses of medications. For
within the ‘frail’ subpopulation.
example, a drug’s reliance on flow- or capacity-limited
pharmacokinetics, as well as its propensity for protein Compliance with Ethical Standards
binding, must be considered before administering drugs
that are largely eliminated by hepatic mechanisms as All authors contributed to this paper and all approved the final ver-
sion. No funding was received for the preparation of this manuscript.
considerations of drug clearance need to be made [7, 12]. Joseph L. Tan, Jacques G. Eastment, Arjun Poudel, and Ruth E. Hubbard
Prodrugs that undergo hepatic metabolism are theoretically declare no conflicts of interests and compliance with ethical standards.
less effective in older people and hence require dose
adjustments, while those drugs metabolised by renal and Appendix
biliary excretion may require lower doses in older people.

Search Strategies
Database: PubMed
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1. Search (aging [tiab] OR ageing [tiab] OR "older person" [tiab] OR "older persons" [tiab] OR
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2. Search (liver [tiab] OR hepatic [tiab]) (768,778)

3. Search (metabolism [tiab] OR detoxification [tiab]) (544,770)

4. Search "pharmaceutical preparations" [MeSH Terms] (605,547)

5. 1 and 2 and 3 and 4 (63)

6. 5 with restrictions: <humans> (33)

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Restricons: Aged from Age Groups
Very elderly from Age Groups
Humans
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2. Search “pharmaceutical preparations” OR medications OR drugs OR medicines (1,009,700)

3. Search metabolism (1,954,915)

4. Search hepatic or liver (1,339,089)

5. 1 AND 2 AND 3 AND 4 AND [English]/lim AND ([aged])/lim OR [very elderly]/lim) AND [humans]/lim
AND [embase]/lim (139)
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Age-Related Changes in Hepatic Function
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