Skip to main content
NCBI home page
Therapeutic Advances in Drug Safety logoLink to Therapeutic Advances in Drug Safety
. 2010 Dec;1(2):65–77. doi: 10.1177/2042098610386281

Drug-induced liver injury in older adults

Sarah J Mitchell 1, Sarah N Hilmer Associate Professor 2,✉
PMCID: PMC4110803  PMID: 25083196

Abstract

Drug-induced liver injury (DILI) is an important cause of hospitalisation and of medication deregistration. In old age, susceptibility to DILI is affected by changes in physiology and increased interindividual variability, compounded by an increased prevalence of disease and the frailty syndrome. While dose-related or predictable DILI reactions are often detected in preclinical trials, the occurrence of rare hypersensitivity or idiosyncratic reactions cannot be reliably predicted from preclinical studies or even by clinical trials. The limited participation of older adults in clinical trials means that the susceptibility of this population to DILI is largely unknown. Vigilance during clinical trials and postmarketing surveillance must be universally practised. A systematic approach should be taken to determine not only which medicines are hepatotoxic and should be removed from the market, but also the hepatotoxicity risks from marketed drugs to consumers with different characteristics, many of whom are older people.

Keywords: ageing, drug-induced liver injury, frailty, idiosyncratic, pharmacovigilance

Introduction

Optimising the safety and efficacy of medications in older people is complex and multi-factorial [Hilmer et al. 2007b]. With old age, there is an increase in disease for which medications may provide benefit. The incidence of serious adverse drug reactions also increases with increasing age, even after controlling for increased medication use [Moore et al. 2007]. Most adverse drug reactions (ADRs) in older people, including drug-induced liver injury (DILI), are dose-related [Routledge et al. 2004].

In this review we describe the epidemiology, mechanisms, detection and management of DILI, with particular concern to old age. In all age groups, an important susceptibility factor for hepatotoxicity is genetic variability. In older people, this may be compounded by the large interindividual variation in response to medications, further increasing the risks of toxicity and poor efficacy [McLachlan et al. 2009]. This is a particular concern in frailty, a condition of increased vulnerability to adverse events [Fried et al. 2001]. Monitoring for clinical response is essential to optimise efficacy and reduce toxicity. However, the detection of adverse effects of medications in older patients may be complicated by nonspecific presentation as geriatric syndromes [Avorn and Shrank, 2008].

Epidemiology

DILI is an important cause of hospital admissions and deregistration of medications [Holt and Ju, 2006]. Hospital admissions for ADRs have increased steadily over the last decade in older Australians [Burgess et al. 2005]. In Spain, 45% of cases of DILI reported from 1994–2004 occurred in patients aged >60 years [Andrade et al. 2005].

Drug-induced hepatotoxicity has been of increasing interest due to the withdrawal of a number of drugs shortly after being put onto the market [Björnsson and Olsson, 2006]. Troglitazone was withdrawn from the market in the UK in 1999 and in US in 2000 [Björnsson and Olsson, 2006]. Lumiracoxib was withdrawn from the market in 2007 by the Australian Therapeutics Goods Association because of reports of serious liver injury, including fulminant liver failure. New Zealand, Canada and the European Union followed suit [Burton, 2007]. A recent systematic investigation by the WHO Collaborating Centre for International Drug Monitoring reported that the five most common drugs associated with fatalities during 1969–1990 were paracetamol, troglitazone, valproate, stavudine and halothane [Björnsson and Olsson, 2006]. After 1990, the most common drug associated with a fatal outcome shifted from halothane (immuno-allergic DILI) to paracetamol (dose-dependant DILI) [Björnsson and Olsson, 2006; Lee, 2003].

Clinical pharmacology in old age and frailty

The increased interindividual variation with ageing makes it difficult to predict safe and effective medication dosage. Impaired clearance of drugs and their metabolites [Hilmer, 2008] is the most significant pharmacokinetic change in ageing. In old age there are decreases in renal function [Hämmerlein et al. 1998], hepatic mass and blood flow [Hilmer et al. 2007b; McLean and Le Couteur, 2004]. Cytochrome-mediated (CYP-mediated) hepatic metabolism is impaired with normal ageing, however most studies suggest that conjugation reactions are maintained in healthy older people but reduced in the older frail [Hilmer, 2008; Wynne, 2005]. Changed body composition (decreased lean body mass, increased fat mass) with ageing affects the volume of distribution and half life of drugs [Hilmer and Ford, 2009; Bales and Ritchie, 2002].

Changes in the pharmacodynamics of drugs in old age is related to changes in drug targets, physiologic reserve and in response to injury [Hilmer, 2008]. Age-related defenestration of the liver sinusoid affects the hepatic disposition of lipoproteins [Hilmer et al. 2005a; Le Couteur et al. 2002] and medications [Mitchell et al. 2010b] and may play a role in autoimmune disease in older people by impeding the interactions between naive T lymphocytes and hepatocytes that are thought to induce immunotolerance [Warren et al. 2006]. Hepatic glutathione content decreases with age in animals [Wang et al. 2003; Stio et al. 1994] and humans [Lang et al. 1992]. Dysregulation of the Kupffer cells (liver macrophages) occurs in old age (Table 1). Basal Kupffer cell numbers and activity are increased in old age [Hilmer et al. 2007a], however the Kupffer cell response to toxic doses of cadmium was decreases in senescent male rats [Yamano et al. 2000]. There is also an age-related dysfunction and reduced biogenesis of mitochondria [López-Lluch et al. 2008].

Table 1.

Physiological changes associated with ageing and frailty that can have an impact on the pharmacokinetics and pharmacodynamics of drugs. Adapted from Mitchell et al. [2009a] and references [Hilmer and Ford, 2009; Hilmer, 2008; López-Lluch et al. 2008; Hilmer et al. 2007a, 2005a; Warren et al. 2006; Wang et al. 2003; Le Couteur et al. 2002, 2001; Hämmerlein et al. 1998; Klotz, 1998; Kinirons et al. 1997; Stio et al. 1994; Lang et al. 1992].

Pharmacokinetic changes
Absorption Distribution Metabolism Elimination
↔ Passive absorption ↓ Plasma albuminh,f ↓ Liver volumea,h,f ↓ Glomerular filtration rateh,f
↓ Protein affinity ↓ Hepatic blood flowa,h,f
↑ α1-acid glycoprotein ↑ Interindividual variabilityh,f
↑ Body fath ↓ First pass metabolismf
↓ Lean and total body massh,f ↑↓ CYP-mediated metabolisma,h,f
↑ Expression and activity of P-glycoprotein in livera ↔ Conjugation reactionsa,h
↓ Conjugation reactions in frail
Pharmacodynamic changes in the liver
Pseudocapillarization of the liver sinusoida,h
↓ Hepatic glutathionea,h
Dysregulation of Kupffer cellsa
Dysregulation of the immune systema,h
Dysregulation of mitochondriaa,h
Open in a new tab

aAnimal studies; hHuman/clinical studies; fPharmacokinetic and/or pharmacodynamic change is accentuated in the frail; ↓: decreased; ↑: increased; ↔: no change.

Frailty is a multidimensional syndrome of loss of reserve which gives rise to vulnerability [Rockwood et al. 2005; Fried et al. 2001]. Frailty is associated with an increased risk of illness and mortality [Bales and Ritchie, 2002], as well as reluctance to prescribe certain medications [Perera et al. 2009]. Table 1 summarizes the pharmacokinetic and pharmacodynamic changes that occur with ageing and frailty. However, few studies have been conducted in older frail adults [Schwartz, 2006; Wynne et al. 1993; Wynne et al. 1990; Wynne et al. 1989].

Mechanisms of DILI

Like other ADRs, DILI can be classified as either Type A predictable or Type B idiosyncratic [Schenker et al. 1999]. The mechanisms are explained in more detail below. The type of liver injury induced by a potential hepatotoxic agent can be classified clinically by the relative rise of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) [Hussaini and Farrington, 2007]. The pathogenesis involves direct hepatotoxicity by the drug or a reactive metabolite, and adverse immune reactions, usually triggered by hepatic damage [Holt and Ju, 2006]. Pathology of DILI includes hepatitis, cholestasis, fibrosis, steatosis, vascular damage or mixed pathologies [Hussaini and Farrington, 2007].

Type A predictable (dose-dependant) or intrinsic DILI and the effect of ageing

Predictable or intrinsic DILI is a dose-dependant injury that affects all individuals at some dose. The latent period after exposure is predictable and liver pathology is often distinctive. Routine animal testing can easily identify intrinsic hepatotoxins [Roth and Ganey, 2010]. Most adverse drug reactions causing admission of older people to hospital are Type A reactions and hence are predictable and potentially preventable. Paracetamol causes dose-dependant hepatotoxicity through the metabolic bio-activation of the parent drug to a toxic metabolite [Roth and Ganey, 2010]. It is responsible for approximately half of the cases of acute liver failure in the United States [Roth and Ganey, 2010].

Ageing and frailty are associated with a loss of reserves and increased state of vulnerability [Rockwood et al. 2005], therefore it is likely that the older frail will be at increased risk of DILI from therapeutic doses of medications. Changes in drug clearance in old age affect the formation and clearance of the toxic metabolites and therefore the susceptibility to DILI [Hilmer et al. 2005b]. Interestingly one determinant of the variability in susceptibility to hepatotoxicity appears to be inflammatory stress [Roth and Ganey, 2010]. Subclinical chronic activation of the immune system in older people [Franceschi et al. 2000] is likely to result in decreased response to injury. However, this is likely to vary between individuals.

Type B idiosyncratic (dose-independent) DILI and the effect of ageing

Idiosyncratic DILI affects only susceptible individuals. The onset is highly variable and the relationship to dose is obscure. It may only occur in individuals who generate an unusual metabolite or develop an allergic response to such a derivative due to some genetic proclivity [Roth and Ganey, 2010; Schenker et al. 1999]. Routine animal testing does not identify idiosyncratic DILI and it is often only detected in postmarketing surveys of larger populations. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market. Examples of idiosyncratic hepatotoxins are the nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac and sulindac [Roth and Ganey, 2010].

Type B idiosyncratic ADRs, such as interstitial nephritis and hepatitis with H2-receptor antagonists, appear to be more common in older people [Fisher and Le Couteur, 2001], and these are not preventable given our current understanding of ageing pharmacology [Hilmer et al. 2005b]. Many Type B reactions can now be explained through polymorphisms in pharmacologic factors and may also be dose dependent [Wilke et al. 2007].

‘The mitochondrial hypothesis’ has been proposed as a mechanism in the development of idiosyncratic DILI [Boelsterli and Lim, 2007]. It implies the gradual accumulation of initially silent mitochondrial injury which, when a critical threshold is reached, abruptly triggers liver injury [Boelsterli and Lim, 2007]. Age-related mitochondrial dysfunction [López-Lluch et al. 2008] may compound this injury. This could explain the delay in idiosyncratic DILI by weeks or months (accumulation of deficits to reach a threshold), and why increasing age is a risk factor (due to duration of exposure or mitochondrial changes in ageing). Female gender is also a risk factor [Boelsterli and Lim, 2007].

Factors influencing susceptibility to DILI

Susceptibility to DILI is multifactorial. The most common factors affecting susceptibility to DILI include: advanced age, gender, genetics, metabolism, immunologic reactions, absorption/distribution, inflammation, co-exposures and nutritional status [Roth and Ganey, 2010] (Table 2). Furthermore the impact of complementary and alternative medicines on liver injury has increased as the use of these medicines has become more common [Lee, 2003; Chitturi and Farrell, 2000b]. In this review we focus on age as a risk factor for DILI. Susceptibility to DILI in older people may be associated with particular medications, pattern of exposure (e.g. higher prevalence of medication use, polypharmacy, drug interactions, cognitive impairment affecting adherence), or age-related changes in pharmacokinetics or pharmacodynamics [Hilmer et al. 2007b]. Figure 1 illustrates the susceptibility to DILI with ageing and frailty using the pharmacologic concept of the dose–response (DR) curve and the therapeutic window.

Table 2.

Risk factors for drug-induced hepatotoxicity. Adapted from Pugh et al. [2009] and references [Kumar et al. 2010; Daly et al. 2009; Myers et al. 2008; Hilmer et al. 2007b; Maddrey, 2005; Schmidt, 2005; Huang et al. 2003; Lee, 2003; Kaplowitz, 2001; Pande et al. 1996; Banks et al. 1995].

Factor Sub grouping Effect of factor on hepatotoxicity Drug examples
Age Children ↑ Valproic acid, salicylates
>60 years ↑ Halothane, isoniazid, paracetamol, diclofenac
Gender Female ↑ Halothane, diclofenac, isoniazid, flucloxacillin
Male ↑ Azathioprine
Nutrition Obesity ↑ Methotrexate, halothane
Fasting ↑ Paracetamol
Excessive alcohol consumption – ↑ Paracetamol, isoniazid
Dose ↑ blood concentration ↑ Paracetamol, aspirin
↑ duration ↑ Methotrexate, vitamin A, flucloxacillin
Other drugs ↑ Rifampicin, pyrazinamide, isoniazid
Hepatitis C, B ↑ HAART therapy, isoniazid
Genetic factors HLA-B*5701 genotype ↑ Flucloxacillin
Slow acetylator ↑ Isoniazid
Open in a new tab

↑, increased; HAART therapy, highly active antiretroviral therapy.

Figure 1.

Figure 1.

Open in a new tab

Susceptibility to intrinsic and idiosyncratic drug-induced liver injury (DILI) with ageing and frailty. With ageing and frailty the susceptibility to intrinsically toxic drugs may change, shifting the dose–response (DR) curve and therapeutic window. Paracetamol is an intrinsically toxic drug and human case reports suggest that hepatotoxicity is increased in old age [Mitchell et al. 2010a; Wynne et al. 1990] with the DR curve shifted to the left (dashed line in (a)). Therefore, pharmacological effect and liver toxicity are more closely related (i.e. at the same dose an older person is more likely to experience toxicity than a younger person). However, animal studies indicate that paracetamol hepatotoxicity is reduced in old age, so the DR curve is shifted to the right (dashed line in (b)) meaning the toxic effect occurs at a higher than therapeutic dose. Drugs that cause idiosyncratic DILI do not cause toxicity in most people; this may be because the DR curve for liver injury lies to the right of the lethal dose of a drug. Inflammatory stress may sensitize the liver to injury from a variety of toxins, resulting in a shift in the DR curve to the left (dashed line in (c)) meaning that for idiosyncratic toxins a hepatotoxic effect is seen in the therapeutic dose range [Roth and Ganey, 2010]. As ageing and frailty are associated with an inflammatory state [Franceschi et al. 2000], they may shift the DR curve to the left resulting in increased sensitivity to idiosyncratic toxins in old age, and this appears to be true for diclofenac [Banks et al. 1995]. However reduced activation of the immune system with ageing and frailty may mean that the DR curve stays in its initial position or shifts even further to the right (dashed line in (d)). This may explain the dual nature of diclofenac hepatotoxicity causing both Type A and Type B DILI [Boelsterli, 2003]. Picture adapted from Roth and Ganey [2010] with references [Boelsterli, 2003; Franceschi et al. 2000; Banks et al. 1995; Rikans and Moore, 1988].

The effect of age on medications commonly associated with DILI and their outcomes

Paracetamol

Paracetamol is the drug that most commonly causes hepatotoxicity [Heaton et al. 2003]. Owing to its dose-related hepatotoxicity in humans and animals, and its clinical relevance, paracetamol is one of the most studied agents causing intrinsic hepatotoxicity [Roth and Ganey, 2010]. Accidental overdose accounts for only 15% of cases in the general population, but accounts for 55% of cases in older adults [Myers et al. 2007]. Emerging case reports indicate that hepatotoxicity may also occur with chronic therapeutic use of paracetamol, even in the absence of risk factors such as chronic alcoholism and malnutrition [Bolesta and Haber, 2002]. Bio-activation of paracetamol to its toxic metabolite via cytochrome P450 (CYP) 2E1, and subsequent binding of the toxic metabolite to liver macromolecules is responsible for hepatocyte damage and death, as described in Table 3 [Prescott, 1983; Jollow et al. 1974; Mitchell et al. 1973]. Liver biopsy reveals a centrilobular necrosis, with periportal sparing and little or no inflammatory reaction [Ward and Alexander-Williams, 1999; Prescott, 1983]. In severe cases acute renal failure may occur [Ward and Alexander-Williams, 1999].

Table 3.

Drugs commonly implicated in DILI, clinical indicators and their change susceptibility in old age and potential explanations.

Drug Mechanism of DILI Clinical Indicator Change in DILI susceptibility with age Potential explanation References
Intrinsic
Paracetamol Saturation of conjugation pathways → ↑ use of the CYP450 pathway → ↑ NAPQI formation and ↑ depletion of hepatic GSH NAPQI reacts with sulphydryl groups on hepatic proteins → hepatocyte damage and death Aminotransferase elevations ↑ Toxicity with age in clinical studies ↓ Toxicity with age in animal studies ? ↓ Hepatic glutathione ? ↓ Immune response ? Age-related ↓ in clearance [Rowden et al. 2006; Prescott, 2000, 1983; Ward and Alexander-Williams, 1999; Kwan et al. 1995; Thomas, 1993; Miner and Kissinger, 1979; Jollow et al. 1974; Mitchell et al. 1973]
Idiosyncratic
Diclofenac Liver microsomes can activate diclofenac into a reactive metabolite(s), which binds covalently to microsomal proteins Diclofenac adducts target mitochondria Aminotransferase elevations ↑ Toxicity with age ? Age-related changes in mitochondria ? Age-related ↓ in clearance [Laine et al. 2009; Naisbitt et al. 2007; Bort et al. 1999; Shen et al. 1999; Banks et al. 1995; Ponsoda et al. 1995]
Isoniazid Metabolic bioactivation of toxic metabolite hydrazine and its monoacetyl derivative by CYP2E1 Mild elevation of liver enzymes in <20% of patients Severe hepatotoxicity in 1–2% of patients ↑ Toxicity with age ↑ Susceptibility for slow acetylator phenotype* ? Change in acetylator status with age [Pugh et al. 2009; Maddrey, 2005; Yue et al. 2004] *[Pugh et al. 2009]
Flucloxacillin Metabolic bioactivation to toxic metabolite via CYP3A4 HLA-B*5701 genotype is a major determinant of DILI ↑ Bilirubin and ALP Prolonged painless jaundice ↑ Toxicity with age ? Preserved CYP3A activity [Daly et al. 2009; Andrews and Daly, 2008; Russmann et al. 2005; Lakehal et al. 2001]
Open in a new tab

↓, decreased; ↔, unchanged;

↑, increased;?, unknown; →, leads to; CYP, cytochrome P450; GSH, glutathione; NAPQI, n-acetyl p-benzoquinone immine; DILI, drug-induced liver injury; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Older age, unintentional overdose, alcohol abuse and underlying liver disease are risk factors for hepatotoxicity with paracetamol overdose [Myers et al. 2008; Schmidt, 2005]. Increasing age is associated with increased time to presentation [Schmidt, 2005], resulting in poorer outcome. Interestingly, in rats the risk of hepatotoxicity from paracetamol decreases with increasing age [Rikans and Moore, 1988]. Paracetamol metabolism and toxicity depend on both ageing and frailty [Mitchell et al. 2010a; Wynne et al. 1990], which is associated with malnutrition [Ward and Alexander-Williams, 1999]. However, the risk of hepatotoxicity from therapeutic doses of paracetamol in older people is not well defined. Older frail hospital inpatients taking therapeutic paracetamol for 5 days do not have an increased risk of raised ALT compared with younger patients, although the clinical implications of such findings are not clear [Mitchell et al. 2010a]. In people aged ≥65 years, the clinical increased risk of paracetamol hepatotoxicity is likely related to dosing that does not account for decreased liver volume with age, to frailty and to malnutrition [Hilmer et al. 2007b]. Pharmacometabolonomics may help predict individuals at risk of paracetamol hepatotoxicity in the future [Winnike et al. 2010].

Diclofenac

Diclofenac is a NSAID widely used for treatment of a variety of rheumatoid disorders. Diclofenac use is associated with raised liver function tests in 10–20% of patients and rarely with idiosyncratic serious hepatotoxicity, for which metabolic risk factors have been identified [Maddrey, 2005; Rostom et al. 2005; Boelsterli, 2003]. Normal ageing appears to be associated with increased risk of hepatotoxicity from diclofenac [Banks et al. 1995] in humans.

Diclofenac is metabolized by the CYP enzymes 2C9 and 3A4, resulting in reactive metabolite(s) that bind to microsomal proteins [Naisbitt et al. 2007; Bort et al. 1999; Shen et al. 1999]. Diclofenac-induced dose- and concentration-dependant liver injury has been demonstrated in rat hepatocytes [Kretzrommel and Boelsterli, 1993]. Mitochondria have also been identified as the target for diclofenac adducts [Ponsoda et al. 1995]. The lack of a suitable animal model for the human situation, means that the pathogenesis of the toxic response in the severe form of diclofenac-induced idiosyncratic hepatotoxicity in humans remains unknown [Boelsterli, 2003]. Table 3 describes the characteristics of diclofenac-induced DILI.

Hepatocellular injury has been reported as the most common form of diclofenac-associated hepatic injury [Banks et al. 1995]. Increasing age and female gender are risk factors [Kaplowitz, 2001; Banks et al. 1995]. Most aminotransferase elevations occur within the first 4–6 months of initiation of diclofenac therapy and resolve with cessation of therapy [Laine et al. 2009]. Symptomatic reporting was the major cause for identification of injury while monitoring was responsible for only 18% of injury being identified [Banks et al. 1995]. This highlights that idiosyncratic DILI does not necessarily occur early in the course of the therapy, and the importance of regular monitoring for liver injury.

It has been suggested that the hepatotoxicity of diclofenac via either direct damage or an idiosyncratic reaction is dose related [Gonzalez-Martin et al. 1997]. However, even the decrease in hepatic clearance in old age does not explain the increased risk of hepatotoxicity from diclofenac at therapeutic doses in older adults [Banks et al. 1995]. Assuming mitochondria are the target for diclofenac adducts [Ponsoda et al. 1995] then dysfunction and reduced biogenesis of mitochondria with ageing [López-Lluch et al. 2008] may explain the increased risk of diclofenac hepatotoxicity in older people. The accumulation of diclofenac adducts could further aggravate the already age-related deficient mitochondria causing increased accumulation of damage which, once a threshold is reached, results in liver damage. As the deficit in mitochondria is varied between individuals, this could explain why there is increased risk of hepatotoxicity with age (increased mitochondrial deficits to begin with meaning the threshold is reached earlier), why hepatotoxicity is not instantaneous on initiation of therapy (mitochondrial deficits need to accumulate over time) and why animal models have been unable to replicate the human response (accumulation of mitochondrial deficits due to environmental factors).

Isoniazid

Isoniazid is one of the most commonly used drugs for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1–2% of patients [Pugh et al. 2009; Yue et al. 2004]. In many patients, continuation of isoniazid is well tolerated and their aminotransferase levels will return to normal or nearly normal levels, representing a hepatic adaptation response [Pugh et al. 2009]. Liver injury from isoniazid seems to be mediated by the toxic metabolite hydrazine and its monoacetyl derivative [Yue et al. 2004]. Risk factors for toxicity include regular to heavy alcohol consumption, induction of CYP2E1 [Maddrey, 2005; Pande et al. 1996], slow acetylators [Pugh et al. 2009; Huang et al. 2003] and female gender [Maddrey, 2005], as described in Table 3.

Theoretically, older adults should experience less isoniazid toxicity due to the reduction in CYP-mediated metabolism in older adults, which is further reduced in the frail [Hilmer, 2008; Wynne, 2005], resulting in less toxic metabolite(s) and therefore less liver damage. However, this is clearly not the case as advanced age is associated with an increased risk of isoniazid hepatotoxicity [Kumar et al. 2010; Maddrey, 2005; Pande et al. 1996]. Interestingly, Schwartz and Verotta have shown that sex and concurrent medications have a greater effect than chronological age in older patient populations for CYP3A substrates [Schwartz and Verotta, 2009; Schwartz, 2006]. Clearance of the CYP3A substrate, atorvastatin, was reduced only in older men and not women [Schwartz and Verotta, 2009]. This gender-specific reduction could explain why female gender is often a risk factor for toxicity, as presumably their CYP enzyme activity is preserved somewhat compared with older males.

Flucloxacillin

Flucloxacillin is a beta-lactam semisynthetic antibiotic used widely in the treatment of Gram-positive bacterial infections, and is widely used in many European countries and Australia for treatment of staphylococcal infection [Daly et al. 2009; Andrews and Daly, 2008]. It has become a common cause of drug-induced cholestasis in Europe, Scandinavia and Australia [Daly et al. 2009]. Liver injury is cholestatic in nature with minimal or no hepatic necrosis. Bile duct abnormalities are seen in most cases while inflammatory reaction is moderate or absent. Repair of bile ducts results in healing, however in some cases severe damage leads to paucity of bile ducts and to biliary cirrhosis and strongly indicates an idiosyncratic, immunologically mediated, hypersensitivity reaction to the drug and/or to a metabolite [Devereaux et al. 1995]. The relatively high frequency of the reaction has suggested that a reactive metabolite 5-hydroxymethylflucloxacillin formed through CYP3A4 metabolism is responsible [Lakehal et al. 2001]. The HLA-B*5701 genotype and a pregnane X receptor polymorphism are major determinants of DILI due to flucloxacillin [Andrews et al. 2010; Daly et al. 2009]. Risk factors include increasing age, prolonged therapy (>14 days) and female gender [Daly et al. 2009; Andrews and Daly, 2008; Russmann et al. 2005; Devereaux et al. 1995], as described in Table 3.

There is a clear increased risk of flucloxacillin-induced DILI with age, with a recent study indicating those aged >60 years were 6.1 times more likely to develop cholestatic liver disease after flucloxacillin exposure than those aged <60 years (95% CI 2.9, 13.0) [Russmann et al. 2005]. Preservation of CYP3A activity in older women [Schwartz and Verotta, 2009; Schwartz, 2006] may play a role, however this needs further investigation.

Detection and management of DILI

While preclinical studies may detect type A (dose-related) DILI, these studies rarely detect type B (idiosyncratic) DILI. The incidence of DILI is usually low, and therefore even large clinical trials are unlikely to estimate the true risk. Hy’s Law states that a combination of elevated ALT and total bilirubin concentration is a strong predictor of the potential for a drug to cause DILI [FDA, 2009; Stevens and Baker, 2009], and has been used by the FDA to identify drugs likely to cause severe liver injury [FDA, 2009]. Increasing the size and diversity of the clinical study population would increase the statistical power to detect adverse outcomes [Stevens and Baker, 2009]. This is important for older people, particularly the frail, who consume a large number of medications and yet are poorly represented in clinical trials [McLean and Le Couteur, 2004].

Laboratory detection

Serum ALT and total bilirubin are the most common biomarkers used to detect and manage hepatocellular injury [Watkins, 2009]. Serum ALT is more liver specific than AST and is a very sensitive detector of hepatocellular necrosis; however it cannot distinguish DILI from necrosis resulting from other causes such as viral hepatitis, alcohol consumption or other unexplainable reasons [Watkins, 2009; Clark et al. 2003; Schenker et al. 1999]. In patients with a priori elevated transaminases this is further complicated due to the lack of guidelines as to what contributes a significant increase [Schenker et al. 1999]. In older people, reduced liver size may mean transaminases do not increase as substantially as in younger people [Elinav et al. 2006; Le Couteur and McLean, 1998].

Monitoring transaminases levels on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications that are known hepatotoxins, such as isoniazid or diclofenac [Lee, 2003]. However, monitoring is seldom performed consistently despite being recommended by guidelines and policies [Mitchell et al. 2009b; Lee, 2003]. Even if it were, there is no guarantee of safeguarding the patient, since many drug reactions develop abruptly.

Management and treatment

Early intervention is essential as the aim of treatment is to prevent progression to acute liver failure. Idiosyncratic reactions necessitate prompt recognition of the symptoms attributable to DILI as this is the key to stopping the drug and reducing the extent of liver injury. The highly variable nature of idiosyncratic symptoms mean this is often not the case [Chitturi and Farrell, 2000a]. Paracetamol remains the only hepatotoxin to have effective pharmacotherapy, N-acetylcysteine (NAC), based on well-established nomograms [Rumack and Matthew, 1975]. The benefit of NAC extends beyond those who have developed fulminant hepatic failure [Chitturi and Farrell, 2000a]. In older people, increased age is associated with increased time to presentation which may be explained in part by the higher proportion of accidental overdose in older patients [Schmidt, 2005]. By the time older adults present, it may be too late to achieve benefit from NAC, despite it being indicated for late presenters (10–24 hours postoverdose) [Chitturi and Farrell, 2000a].

Adjunctive therapy such as corticosteroids or ursodeoxycholic acid is based on anecdotal evidence. Use of corticosteroids can be considered in cases of drug-induced hepatitis that fail to resolve after 6–8 weeks, and particularly in reactions with a presumed immune basis, such as those associated with allopurinol [Chitturi and Farrell, 2000a]. In the case of drug-induced cholestasis, symptomatic measures such as replenishment of fat-soluble vitamins and control of pruritus may help to improve quality of life. There is no convincing evidence that corticosteroid therapy alters the natural history of flucloxacillin-induced DILI [Devereaux et al. 1995]. The pharmacotherapy of end-stage liver disease (diuretics, beta-blockers) is the same as for other causes of liver disease [Chitturi and Farrell, 2000a], however this is not well described in ageing. Older people do, however, suffer more ADRs to beta-blockers and diuretics [Lindley et al. 1992].

Postmarketing surveillance

Drug-induced hepatotoxicity is a rare but important complication that will continue to be problematic with new drugs coming on to the market as well as with established hepatotoxins. Initial clinical trials are not always adequately powered to determine which medications are hepatotoxic [Pugh et al. 2009]. Animal models undoubtedly screen out most potent toxins; however liver injury at extremely high doses in animal models does not necessarily predict problems in humans. There is no animal testing in old age, malnutrition, comorbidity or polypharmacy, which are all part of ageing and the frailty syndrome in humans. The occurrence of rare hypersensitivity or idiosyncratic reactions in humans cannot be reliably predicted at present from preclinical studies. Therefore, vigilance during clinical trials and postmarketing needs to be universally practised.

Spontaneous reporting systems are currently the cornerstone of postmarketing signal detection. However, they are hampered by limitations [Hauben and Aronson, 2007]. In the USA most cases are reported through the FDA MedWatch program through which physicians and pharmacists may voluntarily file written reports [Lee, 2003]. In Sweden reporting of ADRs to the Swedish Adverse Drug Reactions Advisory Committee has been mandatory since 1975 [Björnsson et al. 2005]. In Australia, the new Advisory Committee on the Safety of Medicines replaces and expands on the role of the Adverse Drug Reactions Advisory Committee and focuses on the safety aspects of medicine regulation and the detection of adverse drug reactions, aiming to increase pharmacovigilance. However, the voluntary nature of this reporting is problematic. Strom has proposed an alternative approach whereby new drugs would receive conditional approval by the FDA during which time mandatory postmarketing studies would allow the detection of progressively rarer adverse effects [Strom, 2006].

Conclusion

With the increasing prevalence of older people combined with the increasing prevalence of age-related disease, the consumption of medications by this section of the population is increasing. However, the susceptibility of older people to adverse events and to drug-induced liver disease is highly variable and may be different from that of younger people. Rigorous pharmacovigilance studies are required to portray the risks of DILI and particularly of serious hepatotoxicity in old age. As there is limited information on how to maximise safety and efficacy of medicines in older adults, hospital admissions for ADRs continue to rise. Better understanding of hepatic clearance and of the mechanisms and risks of DILI in old age will contribute to evidence-based prescribing for older people. This will allow for reduced risk of adverse drug reactions and DILI, and improved quality use of medicines in older people.

Funding

This work was supported by a grant from the National Health and Medical Research Council of Australia, and the Geoff and Elaine Penney Ageing Research Unit at The Royal North Shore Hospital.

Conflicts of interest statement

The authors declare no conflict of interest in preparing this manuscript.

References

  1. Andrade R.J., Lucena M.I., Fernandez M.C., Pelaez G., Pachkoria K., Garcia-Ruiz E., et al. (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129: 512–521 [DOI] [PubMed] [Google Scholar]
  2. Andrews E., Armstrong M., Tugwood J., Swan D., Glaves P., Pirmohamed M., et al. (2010) A role for the pregnane X receptor in flucloxacillin-induced liver injury. Hepatology 51: 1656–1664 [DOI] [PubMed] [Google Scholar]
  3. Andrews E., Daly A.K. (2008) Flucloxacillin-induced liver injury. Toxicology 254: 158–163 [DOI] [PubMed] [Google Scholar]
  4. Avorn J., Shrank W.H. (2008) Adverse Drug Reactions in Elderly People: A substantial cause of preventable illness. Bmj 336: 956–957 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bales C.W., Ritchie C.S. (2002) Sarcopenia, weight loss, and nutritional frailty in the elderly. Ann Rev Nutrition 22: 309–323 [DOI] [PubMed] [Google Scholar]
  6. Banks A.T., Zimmerman H.J., Ishak K.G., Harter J.G. (1995) Diclofenac-associated hepatotoxicity: Analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 22: 820–827 [PubMed] [Google Scholar]
  7. Björnsson E., Jerlstad P., Bergqvist A., Olsson R. (2005) Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 40: 1095–1101 [DOI] [PubMed] [Google Scholar]
  8. Björnsson E., Olsson R. (2006) Suspected drug-induced liver fatalities reported to the WHO database. Digest Liver Dis 38: 33–38 [DOI] [PubMed] [Google Scholar]
  9. Boelsterli U.A. (2003) Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Toxicol Appl Pharmacol 192: 307–322 [DOI] [PubMed] [Google Scholar]
  10. Boelsterli U.A., Lim P.L.K. (2007) Mitochondrial abnormalities—a link to idiosyncratic drug hepatotoxicity? Toxicol Appl Pharmacol 220: 92–107 [DOI] [PubMed] [Google Scholar]
  11. Bolesta S., Haber S.L. (2002) Hepatotoxicity associated with chronic acetaminophen administration in patients without risk factors. Ann Pharmacother 36: 331–333 [DOI] [PubMed] [Google Scholar]
  12. Bort R., Macé K., Boobis A., Gómez-Lechón M.-J., Pfeifer A., Castell J. (1999) Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol 58: 787–796 [DOI] [PubMed] [Google Scholar]
  13. Burgess C.L., Holman C.D., Satti A.G. (2005) Adverse drug reactions in older Australians, 1981–2002. Med J Aust 182: 267–270 [DOI] [PubMed] [Google Scholar]
  14. Burton B. (2007) Australian drugs regulator cancels registration of COX 2 inhibitor. BMJ 335(7616): 363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Chitturi S., Farrell G. (2000a) Drug-induced liver disease. Current Treatment Options Gastroenterol 3: 457–462 [DOI] [PubMed] [Google Scholar]
  16. Chitturi S., Farrell G.C. (2000b) Herbal hepatotoxicity: An expanding but poorly defined problem. J Gastroenterol Hepatol 15: 1093–1099 [DOI] [PubMed] [Google Scholar]
  17. Clark J.M., Brancati F.L., Diehl A.M. (2003) The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 98: 960–967 [DOI] [PubMed] [Google Scholar]
  18. Daly A.K., Donaldson P.T., Bhatnagar P., Shen Y., Pe'er I., Floratos A., et al. (2009) HLA-B[ast]5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41: 816–819 [DOI] [PubMed] [Google Scholar]
  19. Devereaux B.M., Crawford D.H.G., Purcell P., Powell L.W., Roeser H.P. (1995) Flucloxacillin associated cholestatic hepatitis—an Australian and Swedish epidemic. Eur J Clin Pharmacol 49: 81–85 [DOI] [PubMed] [Google Scholar]
  20. Elinav E., Ackerman Z., Maaravi Y., Ben-Dov I.Z., Ein-Mor E., Stessman J. (2006) Low alanine aminotransferase activity in older people is associated with greater long-term mortality. J Am Geriatrics Soc 54: 1719–1724 [DOI] [PubMed] [Google Scholar]
  21. FDA (2009) Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical Evaluation. Food and Drug Administration, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf.
  22. Fisher A.A., Le Couteur D.G. (2001) Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists. Drug Safety 24: 39–57 [DOI] [PubMed] [Google Scholar]
  23. Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E. et al. (2000) Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908(1): 244–254. [DOI] [PubMed]
  24. Fried L.P., Tangen C.M., Walston J., Newman A.B., Hirsch C., Gottdiener J., et al. (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56: M146–M156 [DOI] [PubMed] [Google Scholar]
  25. Gonzalez-Martin G., Dominguez A.R., Guevara A. (1997) Pharmacokinetics and hepatotoxicity of diclofenac using an isolated perfused rat liver. Biomed Pharmacother 51: 170–175 [DOI] [PubMed] [Google Scholar]
  26. Hämmerlein A., Derendorf H., Lowenthal D.T. (1998) Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical implications. Clin Pharmacokin 35: 49–64 [DOI] [PubMed] [Google Scholar]
  27. Hauben M., Aronson J.K. (2007) Gold standards in pharmacovigilance—the use of definitive anecdotal reports of adverse drug reactions as pure gold and high-grade ore. Drug Safety 30: 645–655 [DOI] [PubMed] [Google Scholar]
  28. Heaton P.C., Cluxton R.J., Jr, Moomaw C.J. (2003) Acetaminophen overuse in the Ohio Medicaid population. J Am Pharm Assoc 43(6): 680–684 [DOI] [PubMed] [Google Scholar]
  29. Hilmer S.N. (2008) ADME-tox issues for the elderly. Expert Opin Drug Metab Toxicol 4: 1321–1331 [DOI] [PubMed] [Google Scholar]
  30. Hilmer S.N., Cogger V.C., Fraser R., McLean A.J., Sullivan D., Le Couteur D.G. (2005a) Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat. Hepatology 42: 1349–1354 [DOI] [PubMed] [Google Scholar]
  31. Hilmer S.N., Cogger V.C., Le Couteur D.G. (2007a) Basal activity of Kupffer cells increases with old age. J Gerontol A Biol Sci Med Sci 62: 973–978 [DOI] [PubMed] [Google Scholar]
  32. Hilmer, S.N. and Ford, G. (2009) General principles of pharmacology, In: Halter, J.B., Ouslander, J.G., Tinetti, M., Studenski, S., High, K., Asthana, S. et al. (eds). Hazzard’s Geriatric Medicine & Gerontology, 6th ed. McGraw-Hill: USA, pp. 99–117.
  33. Hilmer S.N., McLachlan A.J., Le Couteur D.G. (2007b) Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 21: 217–230 [DOI] [PubMed] [Google Scholar]
  34. Hilmer S.N., Shenfield G.M., Le Couteur D.G. (2005b) Clinical implications of changes in hepatic drug metabolism in older people. Therap Clin Risk Manag 1: 151–156 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Holt M.P., Ju C. (2006) Mechanisms of drug-induced liver injury. AAPS J 8: E48–E54 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Huang Y.-S., Chern H.-D., Su W.-J., Wu J.-C., Chang S.-C., Chiang C.-H., et al. (2003) Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 37: 924–930 [DOI] [PubMed] [Google Scholar]
  37. Hussaini S.H., Farrington E.A. (2007) Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Safety 6: 673–684 [DOI] [PubMed] [Google Scholar]
  38. Jollow D.J., Thorgeirsson S.S., Potter W.Z., Hashimoto H., Mitchell J.R. (1974) Acetaminophen-Induced Hepatic Necrosis. Pharmacology 12: 251–271 [DOI] [PubMed] [Google Scholar]
  39. Kaplowitz N. (2001) Drug-induced liver disorders—implications for drug development and regulation. Drug Safety 24: 483–490 [DOI] [PubMed] [Google Scholar]
  40. Kinirons M.T., Crome P., Kinirons M.T., Crome P. (1997) Clinical pharmacokinetic considerations in the elderly. An update. Clin Pharmacokin 33: 302–312 [DOI] [PubMed] [Google Scholar]
  41. Klotz U. (1998) Effect of age on pharmacokinetics and pharmacodynamics in man. Int J Clin Pharmacol Therapeut 36: 581–585 [PubMed] [Google Scholar]
  42. Kretzrommel A., Boelsterli U.A. (1993) Diclofenac Covalent protein binding is dependent on acyl glucuronide formation and is inversely Related to P450-mediated acute cell injury in cultured rat hepatocytes. Toxicol Appl Pharmacol 120: 155–161 [DOI] [PubMed] [Google Scholar]
  43. Kumar R., Shalimar, Bhatia V., Khanal S., Sreenivas V., Gupta S.D., et al. (2010) Antituberculosis therapy-induced acute liver failure: Magnitude, profile, prognosis, and predictors of outcome. Hepatology 51: 1665–1674 [DOI] [PubMed] [Google Scholar]
  44. Kwan D., Bartle W.R., Walker S.E. (1995) Abnormal serum transaminases following therapeutic doses of acetaminophen in the absence of known risk factors. Digest Dis Sci 40: 1951–1955 [DOI] [PubMed] [Google Scholar]
  45. Laine L., Goldkind L., Curtis S.P., Connors L.G., Yanqiong Z., Cannon C.P. (2009) How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am J Gastroenterol 104: 356–362 [DOI] [PubMed] [Google Scholar]
  46. Lakehal F., Dansette P.M., Becquemont L., Lasnier E., Delelo R., Balladur P., et al. (2001) Indirect cytotoxicity of flucloxacillin toward human biliary epithelium via metabolite formation in hepatocytes. Chem Res Toxicol 14: 694–701 [DOI] [PubMed] [Google Scholar]
  47. Lang C.A., Naryshkin S., Schneider D.L., Mills B.J., Lindeman R.D. (1992) Low blood glutathione levels in healthy aging adults. J Lab Clin Med 120: 720–725 [PubMed] [Google Scholar]
  48. Le Couteur D.G., Cogger V.C., Markus A.M.A., Harvey P.J., Yin Z.-L., Ansselin A.D., et al. (2001) Pseudocapillarization and associated energy limitation in the aged rat liver. Hepatology 33: 537–543 [DOI] [PubMed] [Google Scholar]
  49. Le Couteur D.G., Fraser R., Cogger V.C., McLean A.J. (2002) Hepatic pseudocapillarisation and atherosclerosis in ageing. Lancet 359: 1612–1615 [DOI] [PubMed] [Google Scholar]
  50. Le Couteur D.G., McLean A.J. (1998) The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokin 34: 359–373 [DOI] [PubMed] [Google Scholar]
  51. Lee W.M. (2003) Drug-induced hepatotoxicity. N Engl J Med 349: 474–485 [DOI] [PubMed] [Google Scholar]
  52. Lindley C.M., Tully M.P., Paramsothy V., Tallis R.C. (1992) Inappropriate medication is a major cause of adverse drug reactions in elderly patients. Age Ageing 21: 294–300 [DOI] [PubMed] [Google Scholar]
  53. López-Lluch G., Irusta P.M., Navas P., de Cabo R. (2008) Mitochondrial biogenesis and healthy aging. Exp Gerontol 43: 813–819 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Maddrey W.C. (2005) Drug-induced hepatotoxicity: 2005. J Clin Gastroenterol 39(4 Suppl. 2): S83–S89 [DOI] [PubMed] [Google Scholar]
  55. McLachlan A.J., Hilmer S.N., Le Couteur D.G. (2009) Variability in response to medicines in older people: phenotypic and genotypic factors. Clin Pharmacol Therapeut 85: 431–433 [DOI] [PubMed] [Google Scholar]
  56. McLean A.J., Le Couteur D.G. (2004) Aging biology and geriatric clinical pharmacology. Pharmacol Rev 56: 163–184 [DOI] [PubMed] [Google Scholar]
  57. Miner D.J., Kissinger P.T. (1979) Evidence for the involvement of N-acetyl-p-quinoneimine in acetaminophen metabolism. Biochem Pharmacol 28: 3285–3290 [DOI] [PubMed] [Google Scholar]
  58. Mitchell J.R., Jollow D.J., Potter W.Z., Davis D.C., Gillette J.R., Brodie B.B. (1973) Acetaminophen-induced hepatic necrosis I. Role of drug metabolism. J Pharmacol Exp Ther 187: 185–194 [PubMed] [Google Scholar]
  59. Mitchell S.J., Hilmer S.N., McLachlan A.J. (2009a) Clinical pharmacology of analgesics in old age and frailty. Rev Clin Gerontol 19: 103–118 [Google Scholar]
  60. Mitchell S.J., Hilmer S.N., Murnion B.P., Matthews S. (2010a) Hepatotoxicity of therapeutic short-course paracetamol in hospital inpatients: impact of ageing and frailty. J Clin Pharm Therapeut. in press [DOI] [PubMed] [Google Scholar]
  61. Mitchell S.J., Huizer-Pajkos A., Cogger V.C., McLachlan A.J., Le Couteur D.G., Hilmer S.N. (2010b) Poloxamer 407 increases the recovery of paracetamol in the isolated perfused rat liver. J Pharmaceut Sci. in press [DOI] [PubMed] [Google Scholar]
  62. Mitchell S.J., Murnion B.P., Matthews S.T., Hilmer S.N. (2009b) Compliance with paracetamol prescribing policies at a Sydney hospital. J Pharm Pract Res 39: 124–129 [Google Scholar]
  63. Moore T.J., Cohen M.R., Furberg C.D. (2007) Serious adverse drug events reported to the Food and Drug Administration, 1998–2005. Arch Intern Med 167(16): 1752–1759 [DOI] [PubMed] [Google Scholar]
  64. Myers R.P., Li B., Fong A., Shaheen A.A., Quan H. (2007) Hospitalizations for acetaminophen overdose: a Canadian population-based study from 1995 to 2004. BMC Public Health 7: 143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Myers R.P., Shaheen A.A., Li B., Dean S., Quan H. (2008) Impact of liver disease, alcohol abuse, and unintentional ingestions on the outcomes of acetaminophen overdose. Clin Gastroenterol Hepatol 6: 918–925 quiz 837 [DOI] [PubMed] [Google Scholar]
  66. Naisbitt D.J., Sanderson L.S., Meng X.L., Stachulski A.V., Clarke S.E., Park B.K. (2007) Investigation of the immunogenicity of diclofenac and diclofenac metabolites. Toxicol Lett 168: 45–50 [DOI] [PubMed] [Google Scholar]
  67. Pande J.N., Singh S.P.N., Khilnani G.C., Khilnani S., Tandon R.K. (1996) Risk factors for hepatotoxicity from antituberculosis drugs: a case–control study. Thorax 51: 132–136 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Perera V., Bajorek B.V., Matthews S., Hilmer S.N. (2009) The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing 38: 156–162 [DOI] [PubMed] [Google Scholar]
  69. Ponsoda X., Bort R., Jover R., Gómez-lechón M.J., Castell J.V. (1995) Molecular mechanism of diclofenac hepatotoxicity: Association of cell injury with oxidative metabolism and decrease in ATP levels. Toxicol In Vitro 9: 439–444 [DOI] [PubMed] [Google Scholar]
  70. Prescott L.F. (1983) Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 25: 290–314 [DOI] [PubMed] [Google Scholar]
  71. Prescott L.F. (2000) Therapeutic misadventure with paracetamol: fact or fiction? Am J Therapeut 7: 99–114 [DOI] [PubMed] [Google Scholar]
  72. Pugh A.J., Barve A.J., Falkner K., Patel M., McClain C.J. (2009) Drug-induced hepatotoxicity or drug-induced liver injury. Clin Liver Dis 13: 277. [DOI] [PubMed] [Google Scholar]
  73. Rikans L.E., Moore D.R. (1988) Acetaminophen hepatotoxicity in aging rats. Drug Chem Toxicol 11: 237–247 [DOI] [PubMed] [Google Scholar]
  74. Rockwood K., Song X., MacKnight C., Bergman H., Hogan D.B., McDowell I., et al. (2005) A global clinical measure of fitness and frailty in elderly people. CMAJ 173: 489–495 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Rostom A., Goldkind L., Laine L. (2005) Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol 3: 489–498 [DOI] [PubMed] [Google Scholar]
  76. Roth R.A., Ganey P.E. (2010) Intrinsic versus idiosyncratic drug-induced hepatotoxicity—two villains or one? J Pharmacol Exp Therapeut 332: 692–697 [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Routledge P.A., O'Mahony M.S., Woodhouse K.W. (2004) Adverse drug reactions in elderly patients. Br J Clin Pharmacol 57: 121–126 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Rowden A.K., Norvell J., Eldridge D.L., Kirk M.A. (2006) Acetaminophen Poisoning. Clin Lab Med 26: 49–65 [DOI] [PubMed] [Google Scholar]
  79. Rumack B.H., Matthew H. (1975) Acetaminophen poisoning and toxicity. Pediatrics 55: 871–876 [PubMed] [Google Scholar]
  80. Russmann S., Kaye J.A., Jick S.S., Jick H. (2005) Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: Cohort study using data from the UK General Practice Research Database. Br J Clin Pharmacol 60: 76–82 [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Schenker S., Martin R.R., Hoyumpa A.M. (1999) Antecedent liver disease and drug toxicity. J Hepatol 31: 1088–1097 [DOI] [PubMed] [Google Scholar]
  82. Schmidt L.E. (2005) Age and paracetamol self-poisoning. Gut 54: 686–690 [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Schwartz J.B. (2006) Erythromycin breath test results in elderly, very elderly, and frail elderly persons. Clin Pharmacol Ther 79(5): 440–448 [DOI] [PubMed] [Google Scholar]
  84. Schwartz J.B., Verotta D. (2009) Population analyses of atorvastatin clearance in patients living in the community and in nursing homes. Clin Pharmacol Therapeut 86: 497–502 [DOI] [PubMed] [Google Scholar]
  85. Shen S., Marchick M.R., Davis M.R., Doss G.A., Pohl L.R. (1999) Metabolic activation of diclofenac by human cytochrome p450 3a4: role of 5-hydroxydiclofenac. Chem Res Toxicol 12: 214–222 [DOI] [PubMed] [Google Scholar]
  86. Stevens J.L., Baker T.K. (2009) The future of drug safety testing: expanding the view and narrowing the focus. Drug Discov Today 14: 162–167 [DOI] [PubMed] [Google Scholar]
  87. Stio M., Iantomasi T., Favilli F., Marraccini P., Lunghi B., Vincenzini M.T., et al. (1994) Glutathione metabolism in heart and liver of the aging rat. Biochim Biol Cell 72: 58–61 [DOI] [PubMed] [Google Scholar]
  88. Strom B.L. (2006) How the US drug safety system should be changed. JAMA 295: 2072–2075 [DOI] [PubMed] [Google Scholar]
  89. Thomas S.H. (1993) Paracetamol (acetaminophen) poisoning. Pharmacol Ther 60: 91–120 [DOI] [PubMed] [Google Scholar]
  90. Wang H., Liu H., Liu R.-M. (2003) Gender difference in glutathione metabolism during aging in mice. Exp Gerontol 38: 507–517 [DOI] [PubMed] [Google Scholar]
  91. Ward B., Alexander-Williams J.M. (1999) Paracetamol revisited: a review of the pharmacokinetics and pharmacodynamics. Acute Pain 2: 139–149 [Google Scholar]
  92. Warren A., Le Couteur D.G., Fraser R., Bowen D.G., McCaughan G.W., Bertolino P. (2006) T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44: 1182–1190 [DOI] [PubMed] [Google Scholar]
  93. Watkins P.B. (2009) Biomarkers for the diagnosis and management of drug-induced liver injury. Sem Liver Dis 29: 393–399 [DOI] [PubMed] [Google Scholar]
  94. Wilke R.A., Lin D.W., Roden D.M., Watkins P.B., Flockhart D., Zineh I., et al. (2007) Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6: 904–916 [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Winnike J.H., Li Z., Wright F.A., Macdonald J.M., O'Connell T.M., Watkins P.B. (2010) Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin Pharmacol Ther 88: 45–51 [DOI] [PubMed] [Google Scholar]
  96. Wynne H. (2005) Drug metabolism and ageing. J Br Menopause Soc 11: 51–56 [DOI] [PubMed] [Google Scholar]
  97. Wynne H.A., Cope L.H., Herd B., Rawlins M.D., James O.F., Woodhouse K.W. (1990) The association of age and frailty with paracetamol conjugation in man. Age Ageing 19: 419–424 [DOI] [PubMed] [Google Scholar]
  98. Wynne H.A., Cope L.H., James O.F., Rawlins M.D., Woodhouse K.W. (1989) The effect of age and frailty upon acetanilide clearance in man. Age Ageing 18: 415–418 [DOI] [PubMed] [Google Scholar]
  99. Wynne H.A., Yelland C., Cope L.H., Boddy A., Woodhouse K.W., Bateman D.N. (1993) The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide. Age Ageing 22: 354–359 [DOI] [PubMed] [Google Scholar]
  100. Yamano T., DeCicco L.A., Rikans L.E. (2000) Attenuation of cadmium-induced liver injury in senescent male Fischer 344 rats: role of Kupffer cells and inflammatory cytokines. Toxicol Appl Pharmacol 162: 68–75 [DOI] [PubMed] [Google Scholar]
  101. Yue J., Peng R.X., Yang J., Kong R., Liu J. (2004) CYP2E1 mediated isoniazid-induced hepatotoxicity in rats. Acta Pharmacol Sin 25: 699–704 [PubMed] [Google Scholar]

Articles from Therapeutic Advances in Drug Safety are provided here courtesy of SAGE Publications

RESOURCES