Current Drug Metabolism, 2011, 12, 601-610
601
Age-Related Changes in Pharmacokinetics Shaojun Shi*,1 and Ulrich Klotz2,* 1
Department of Pharmacy of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China, 2Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Germany Abstract: Ageing is characterized by a progressive decline in the functional reserve of multiple organs and systems, which can influence drug disposition. In addition, comorbidity and polypharmacy are highly prevalent in the elderly. As ageing is associated with some reduction in first-pass metabolism, bioavailability of a few drugs can be increased. With ageing body fat increases and total body water as well as lean body mass decrease. Consequently, hydrophilic drugs have a smaller apparent volume of distribution (V) and lipophilic drugs have an increased V with a prolonged half-life. Drugs with a high hepatic extraction ratio display some age-related decrease in systemic clearance (CL), but for most drugs with a low hepatic extraction ratio, CL is not reduced with advancing age. In general, activities of cytochrome P450 enzymes are preserved in normal ageing and the genetic influence is much more striking than age effects. Drug transporters play an important role in pharmacokinetic processes, but their function and pharmacology have not yet been fully examined for agerelated effects. One third of elderly persons show no decrease in renal function (GFR>70 mL/min/1.73 m2). In about two thirds of elderly subjects, the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors. In the elderly a large interindividual variability in drug disposition is particularly prominent. In conclusion, the complexity of interactions between comorbidity, polypharmacy, and age-related changes in pharmacokinetics (and pharmacodynamics) justify the old and well-known dosing aphorism "start low, go slow" for aged individuals.
Keyword: Elderly; pharmacokinetics; metabolism; cytochrome P450; transporter; clearance. INTRODUCTION The ageing population (65 years or older) represents a global phenomenon, as it is unprecedented, pervasive, profound, and enduring. Since 1950, the population of older persons has been rising steadily starting from 8% in 1950 to 11% in 2009, and it is expected to reach 22% in 2050. The fastest growing proportion is that of the oldest-old, that means, those aged 80 years or over. This part is currently increasing at a rate of 4% per year. By 2050, it is expected that approximately 1 individual among every 5 older subjects is 80 years or older [1]. Ageing involves a progressive decline in the functional reserve of multiple organs and systems. Since the prevalence of chronic diseases increases with age, ageing is associated with an increase in comorbidity, a reduction in the tolerance to stress and drugs, all contributing to the complexity of this population [2, 3]. In elderly subjects the high comorbidity will lead to a global increase in mortality. Furthermore, in the elderly polypharmacy is highly prevalent due to an increased number of disease states. The elderly take, on average, 2 to 5 prescribed medications on a regular basis and polypharmacy occurs in 20-50% of patients, which is a leading cause of their drug-related problems [4, 5]. Thus, due to the increased consumption of medications and higher comorbidity, the elderly are at a significant risk of exposure to an inappropriate drug intake [6, 7]. Adverse drug reactions (ADRs) are more frequent and more serious in the elderly and drug interactions often occur [7, 8]. ADRs are observed 2-3 times more frequent in older than in younger persons and account in the elderly for 5-17% of all hospital admissions [9]. It is generally accepted that frailty is an important issue in the treatment of the elderly. The frail elderly represents a subgroup in whom not age per se but multiple disease states will primarily account for the observed changes in pharmacokinetic and pharma*Address correspondence to these authors at the Department of Pharmacy of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, People's Republic of China; Tel: +86(027)/8572-6073; Fax: +86(027)/8572-6192; E-mail: sjshicn@163.com; Dr. Margarete Fischer-Bosch Institut fĂźr Klinische Pharmakologie, D-70376 Stuttgart, Auerbachstr. 112, Germany; Tel: +49 (0)711/8101-3702; Fax: +49 (0)711/85 92 95; E-mail: ulrich.klotz@ikp-stutktgart.de 1389-2002/11 $58.00+.00
codynamic properties. Therefore, when considering the impact of ageing one has to differentiate the group of fit elderly from that of frail elderly. Those who are frail are at increased risk of death, institutionalization and worsening disability [10, 11]. Comorbidity, polypharmacy, frailty, and disability may occur in elderly patients as separate or concomitant entities, and their multidimensional assessment should guide clinical decisions. In the elderly, the appropriate and rational use of medications is a matter of growing social and medical concern. In the elderly better understanding of age-related physiological changes and their impact on pharmacokinetics is essential for a safe and effective therapy [12-14]. In the past, several comprehensive reviews have already focused on age-related physiological, pharmacokinetic, pharmacodynamic changes and ADRs [15-19]. The present review will extract from numerous recently published studies the actual evidence whether there are age-related changes in pharmacokinetics, and if so, whether they are of clinical importance, which would necessitate dosage modifications in the elderly. AGE – RELATED PHYSIOLOGICAL AND PHARMACOKINETIC CHANGES Age-related physiological changes will affect body systems and can alter pharmacokinetic processes in different ways (Table 1). Subsequently the effects of drugs might be modified. In the following sections, we will outline general principles and provide a few examples how ageing can affect the absorption, distribution, metabolism and excretion (ADME) of drugs. ABSORPTION With ageing, there seems to be an increase in gastrointestinal (GI) disorders and some subtle changes have been observed in the GI tract [20, 21]. Although an increased prevalence of several GI disorders (e.g. dyspepsia, diarrhea, and constipation) occurs in the elderly, ageing per se appears to have only a minor direct effect on most GI functions, apparently because of the functional reserve capacity of the GI tract [22]. It is still controversially discussed whether gastric emptying changes with ageing [23]. Madsen and Graff reported no influence of advanced age on gastric emptying [24], whereas Shimamoto et al. showed that in the elderly postprandial peristalsis and gastric contractile force were reduced [25]. Š 2011 Bentham Science Publishers
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Table 1.
Shi and Klotz
Age-related Physiological Changes and Their Pharmacokinetic Consequences
Parameter Absorption
Change Increased gastric pH Delayed gastric emptying
Effect Slightly decreased absorption (rarely clinically significant)
Reduced splanchnic blood flow Decreased absorption surface Distribution
Increased body fat
Increased V and t1/2 of lipophilic drugs
Decreased lean body mass
Metabolism
Excretion
Decreased total body water
Increased plasma concentration of hydrophilic drugs
Decreased serum albumin
Increased free fraction in plasma of highly protein-bound acidic drugs
Increased 1-acid glycoprotein
Decreased free fraction of basic drugs
Decreased hepatic blood flow
First-pass metabolism can be less effective
Decreased hepatic mass
Phase I metabolism of some drugs might be slightly impaired; phase II metabolism is restored
Decreased renal blood flow Decreased glomerular filtration rate
Renal elimination of drugs can be impaired to a variable extent
Between 1920 and 1980, many retrospective studies suggested that gastric acid secretion declined with ageing. In contrast to common statements, one study showed that almost 90% of elderly people (> 65 years) were able to acidify gastric contents. Of those who were consistent hyposecretors, most demonstrated serum markers of atrophic gastritis [26]. It has been indicated that in Helicobacter pylori-negative subjects advancing age had no influence on gastric acid secretion, while in Helicobacter pylori-positive patients it decreased because of the elevated prevalence of fundic atrophic gastritis with ageing [27, 28]. In addition, ageing is associated with a decrease in splanchnic blood flow and a smaller bowel surface area [29]. In the elderly absorption, if accomplished by passive diffusion, is probably unchanged for most substrates, such as the majority of oral antiarrhythmic drugs [30]. However, increasing evidence supports the idea that in the epithelial cells of the GI tract drug uptake and extrusion are transporter-mediated and such active transfer processes are rather the rule than the exception [31-33]. The absorption of vitamin B12, iron, calcium, magnesium, leucine – accomplished by active transport mechanisms - is apparently impaired in the elderly [34]. However, the effect of ageing on the expression and function of these GI transporters has not yet been reported. FIRST - PASS METABOLISM AND BIOAVAILABILITY When considering oral bioavailability, presystemic elimination by the intestinal mucosa and during first pass through the liver has to be taken into account (see Fig. 1). Ageing is associated with some reduction in first-pass metabolism that might be due to a decrease in liver mass and perfusion [35]. Bioavailability and consequently plasma concentrations of some drugs undergoing extensive first-pass metabolism, such as propranolol and labetalol, can be significantly increased [36, 37]. However, for other high clearance (CL) drugs like verapamil [38] or propafenone [39], the bioavailability is similar between healthy young and old subjects. On the other hand, the first-pass activation of some prodrugs, e.g. ACE inhibitors enalapril and perindopril, might be slowed down or reduced which may result in a decrease in bioavailability [40]. The transdermal route is especially useful for drugs like buprenorphine that have limited bioavailability if given orally. In the
elderly transdermal drug administration is an ideal therapeutic approach for chronic pain and some neurological disorders because it provides sustained effective plasma levels, it is simple to use, and it may reduce systemic adverse effects [41]. In the elderly, transdermal absorption of fentanyl has been thought to be decreased, resulting in dose adjustments, whereas absorption of transdermal buprenorphine is little affected by age [42]. However, in the elderly most transdermal devices still require long-term evaluation to understand better how age-related skin changes might affect drug absorption. DISTRIBUTION Significant changes in body composition occurring with advancing age are summarized in Fig. 2 [43, 44]. Recently, it has been proposed that reductions in the mass of individual organs/tissues can contribute to a reduction in resting metabolic rate that in turn promotes changes in body composition favoring increased fat mass and reduced fat-free mass with ageing [45]. As body fat increases and total body water as well as lean body mass decrease, polar drugs that are mainly water-soluble, such as digoxin, ethanol, theophylline, and aminoglycosides, tend to have a smaller apparent volume of distribution (V) and subsequently plasma concentrations will increase [46]. On the other hand, nonpolar compounds tend to be lipid-soluble (e.g. diazepam), so in the elderly V increases and half-life (t1/2) is prolonged [47]. There is some correlation (P = 0.053) between lipophilicity of drugs and the effect of ageing on V [34]. The term V determines the loading dose required to initiate therapy and loading doses are calculated based on the desired steady-state blood level and V: Loading dose (mg/kg) = Desired blood concentration (mg/L) Volume of distribution (L/kg) Therefore, hydrophilic drugs such as digoxin and aminoglycosides will have initially a lower dose requirement [48]. However, for most drugs these age-related changes in body composition will not have a major effect on V and adjustment of loading doses is unlikely to be important.
Pharmacokinetic Changes in the Elderly
Div
Current Drug Metabolism, 2011, Vol. 12, No. 7 x
AUCpo
Dpo x AUCiv
= F = fabs x membrane & flow limitations (permeability) gastric pH* GI-motility drug transporters (P-gp) physicochemical properties & formulation of drug
603
FG x FH first-pass effects (especially for high-CL drugs or substrates of CYP3A4 and P-gp)
* with achlorhydria extent of absorption decreased for itraconazole, ketoconazole, iron, calcium carbonate increased for alendronate * with achlorhydria (induced by proton pump inhibitors) extent of absorption decreased for itraconazole, ketoconazole, iron, calcium carbonate; increased for alendronate Fig. (1). Putative factors that will affect drug absorption or oral bioavailability and that might be altered, to some extent, in the elderly (according to Klotz, 2009 [15]).
increase in
decrease in
decrease in
decrease in
body fat
plasma volume
total body water
extracellular body fluid
8%
17 %
40 %
35 %
20 years 65 – 80 years Fig. (2). Age-dependent changes in body composition (according to Klotz, 2009 [15]).
Apart from changes in body composition, there are minor agerelated changes in plasma protein binding [49]. In the elderly serum albumin concentrations can be slightly decreased or remain unchanged; 1-acid glycoprotein tends to be increased with advancing age [49]. These alterations are generally not attributed to age per se, but rather to pathophysiological changes or disease states that may occur more frequently in the elderly [50]. Changes in plasma proteins binding might be clinically relevant only for very highly bound drugs with a small V and a narrow therapeutic index. In such cases a small increase in the free drug concentration might have pharmacodynamic consequences. Although plasma protein binding might contribute to drug interactions, it is regarded to be of little clinical relevance, because the initial and transient effect of protein binding on free plasma concentration is rapidly compensated by increased elimination [50].
METABOLISM General Considerations Although almost every tissue/organ like intestinal wall, lung, skin, and kidney, has some ability to metabolize drugs, the liver represents the principal organ of drug metabolism [51]. The vast majority of drugs has to be biotransformed by several cytochrome P450 (CYP)-dependent phase I reactions (e.g. oxidation, reduction) and/or phase II pathways (e.g. glucuronidation, acetylation, and sulfatation). Some drugs are metabolized by phase I and followed by phase II reactions, but many are metabolized by only one of these types of reactions [51]. More recently, the interdependence of both drug metabolism and transport on the disposition of drugs has gained considerable attention, and has been termed “transportmetabolism interplay� [52, 53]. Acting alone, in concert with each
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other or by compensatory mechanisms they can affect the pharmacokinetics of a drug as well as drug interactions, as illustrated in Fig. (3) for inhibitors of CYP3A and P-glycoprotein (P-gp). Dependent on the inhibitory potential of a drug for both systems the final consequences for drug removal from the body are difficult to predict. These transport processes and the oxygen supply (required for phase I reactions) to the hepatocytes might demonstrate some age dependencies (caused by age-related changes of membrane structures). However, so far such data are not yet available [15]. The liver has a remarkable ability to regenerate and to maintain its function during the ageing process. However, there are subtle changes on a cellular and physiological level which can reduce the overall function of the liver. Increasing age is associated with a decrease in hepatic volume of approximately 20 to 30% [54] as well as a reduction in hepatic blood flow of approximately 20 to 50% [55]. These alterations can affect especially the elimination of highCL drugs. However, in the elderly hepatocyte volume remains unchanged. Furthermore, there are no specific age-related liver diseases and routine clinical tests of liver function do not change significantly with advancing age, but age can affect the course and prognosis of some liver disorders [56, 57]. Whether the metabolic CL of a drug is decreased or unchanged with advancing age has been attributed to the property of high or low extraction of the drug by the liver. Some drugs with a high extraction ratio and a high intrinsic CL (“blood flow-limited metabolism”) are rapidly metabolized in the hepatocytes and the rate of drug loss is limited by hepatic blood flow. They can display some age-related decrease in metabolic CL. On the other hand, the metabolic CL of drugs with low hepatic extraction is in most cases not reduced, since it is not dependent on hepatic blood flow but primarily on the enzyme activity in the liver (“capacity-limited metabolism”)[34]. However, changes in hepatic blood flow and intrinsic CL do not provide a satisfactory explanation for the minor (about 20%) age-dependent reduction of hepatic metabolism of some drugs (e.g. antipyrine and theophylline) [58]. In vitro Findings According to in vitro data, no age-related changes in hepatic microsomal protein content, the activities of NADPH CYP reductase, aldrin epoxidation, 7-ethoxycoumarin-O-deethylation, epoxide hydrolase, and aspirin esterase have been reported [34, 58, 59]. Likewise, in the range of 10-85 years the content and activities of
various CYP enzymes from liver microsomal preparations did not decline with advancing age [60-62]. The effects of age on CYP activities in human liver microsomes are shown in Fig. (4). The subjects were divided into three age groups. It is apparent that in liver microsomes from donors of all ages CYP activity (e.g. CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A11) is highly variable, and there are no statistically significant differences in these activities between the age group of 20-60 years and the group over 60 years. Likewise, in the activities of CYP2D6, CYP2E1, CYP3A4, and UDPglucuronosyltransferases in human hepatocytes, no age-related changes have been seen [63]. All these findings would suggest that in the elderly drug metabolism appears to be quite well preserved, at least up to 80 years. In this context it should be emphasized that for ethical reasons it is difficult to collect healthy liver tissue. Therefore, most of the in vitro results were obtained from subjects providing liver biopsies for diagnosis of some suspected hepatic pathology. Clinical Background Despite abundant animal literature showing an age-related decline in CYP content [64], in man, the effect of age on the various CYPs is controversially discussed [64, 65]. It is generally accepted that CYP enzyme activity is preserved in normal ageing, although in frail older people a decline has been noted, as well as in association with liver disease, cancer, trauma, sepsis, critical illness, and renal failure [66]. Several studies concluded that activities of several CYP species were not reduced with age per se and there were no changes in the enzyme affinity for their substrates [66]. Furthermore, a putative reduced hepatic elimination with advancing age was most likely due to reduction in liver size and blood flow. Studies with Probe Drugs The CYP3A subfamily is especially prominent for the metabolic capacity as it is responsible for the elimination of more than 60% of all metabolized drugs. In man, the erythromycin breath test (ERBT) has been widely used as a phenotypic measure of CYP3A activity, as well as its modulation by inhibitors or inducers. However, it reflects partly also other CYP activities and P-gp function [67, 68]. In 60 subjects between 65 and 101 years the percentage of 14 CO2 excreted per hour (derived from a test dose of radiolabelled erythromycin) was similar in the elderly, either frail or nonfrail, if compared to a large group (n = 199) of controls (age range 20–60
Potent P-gp Inhibitors
Strong CYP3A Inhibitors Weak P-gp Inhibitor: z
Conivaptan
z z z z
Non P-gp Inhibitors: z z z z
Ritonvir (200 mg) Voriconazole Nefazodone Telithromycin
z z
Itraconazole Ritonavir (400 mg) Lopinavir Itraconazole Clarithromycin Ketoconazole
Moderate CYP3A Inhibitors: z z
Weak CYP3A4 Inhibitors: z z z z z
Fig. (3). Metabolizing enzyme transporter interplay (according to Zhang et al., 2009[53]).
Erythromycin Verapamil
Quinidine Ranolazine Amiodarone Azithromycin Felodipine
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(75 mg bid for 15 days)
605
11 young (32 ± 5 y.) 12 elderly (68 ± 2 y.)
(200 mg bid for 15 days)
Fig. (4). Effects of age on CYP activity in human liver microsomes (n refers to the different determinations of the particular CYP). No statistically significant differences were determined by linear regression analysis (data from Parkinson et al., 2004[63]).
years). The ERBT indicated that age from 65 to 101 years did not affect the results. However, elimination was faster in women versus men (P < 0.002), faster in frail versus nonfrail patients (P = 0.01), and faster in those receiving CYP3A inducers versus those without inducers (P = 0.0007). Thus, CYP3A4 inducibility is preserved with ageing [69]. Similar results have been shown earlier with the inducer rifampicin and propafenone which is metabolized by CYP3A4, CYP2D6, CYP1A2 and phase II reactions [39]. Midazolam is widely used as a short-acting benzodiazepine and it represents a sensitive and recommended probe drug for investigating CYP3A4 activity [70]. Besides an early study indicating that only elderly man had a significantly reduced (on average, 44%) CL of midazolam [71], other studies showed unequivocally that CL was similar in the young and the old (>65 years) populations tested [72, 73]. In a comprehensive study with 396 subjects between 60 and 95 years (mean age: 72.1 years), consumption of drugs that act on CYP systems was observed in 61.6% of the elderly individuals. Proton pump inhibitors (PPIs) and fluoxetine were among the most frequently used drugs [74]. It is generally accepted that omeprazole represents a valid probe for CYP2C19 [75, 76]. A recent study in Japanese subjects investigated the effect of ageing on the relationship between the CYP2C19 genotype and omeprazole’s pharmacokinetics [77]. Importantly, the elderly extensive metabolizers (EMs) showed a wide variability in their CYP2C19 activity and they were phenotypically closer to the poor metabolizers (PMs) than the young EMs compared to the young PMs. For example, the increase of AUC for this PPI was more pronounced (about 2-fold) in elderly EMs and intermediate metabolizers (IMs)than in elderly PMs. Thus, when studying age effects for CYP2C19 substrates, all subjects have to be differentiated according to their defined genotype, which has much more impact than ageing per se. One study assessed the pharmacokinetics of fluoxetine and norfluoxetine on CYP2C19 in 14 young and 16 elderly subjects [78]. It was found that in elderly subjects norfluoxetine plasma levels were 22% lower (P < 0.05), with comparable decreases in AUC0-24 and Cmax. When compared to young subjects, in the elderly volunteers t1/2 was longer for fluoxetine (5.0 vs. 4.0 days) and for norfluoxetine (20 vs. 15 days). CYP2C9 is an important drug-metabolizing enzyme, e.g. for warfarin [79], some anticonvulants [80], or traditional nonsteroidal antiinflammatory drugs (tNSAIDs) [81]. In 300 frail elderly inpa-
tients (mean age 86.7 years) it was demonstrated that overall contribution of genetic factors, which accounted for about one-fourth of the interindividual variability in warfarin maintenance dose, was lower than that reported in young patients [79]. As summarized in Fig. (5), the influence of age and CYP2C9 genotype on the steadystate disposition of the standard NSAID diclofenac and the new COX-2 selective inhibitor celecoxib have been compared [81]. It is apparent that age and CYP2C9 genotype did not significantly affect the steady-state disposition of both drugs. Besides CYP2C9, under steady-state conditions CYP3A4 will be a major metabolic contributor [82]. CYP2D6 is of great importance for metabolism; about 20–25% of drugs are metabolized by this enzyme [83]. A recent study in 111 genotyped patients clarified the effects of CYP2D6 genotype on age-related changes in flecainide’s metabolism [84]. The results suggested that metabolic ratio (MR) was higher in elderly patients ( 70 years) than in middle-aged patients (<70 years). In elderly patients the increase of MR differed among CYP2D6 genotypes: 1.6-fold in heterozygous (het)-EMs, 1.5-fold in IMs/PMs, and no change in homozygous (hom)-EMs. Patients characterized as hetEMs and IMs/PMs showed some age-related reduction in flecainide elimination because in these genotypes metabolism was taken over by CYP1A2, whose activity decreases with age [84]. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is metabolized by CYP1A2 and CYP2D6. In 10 healthy young adults, 10 healthy elderly subjects, and 10 elderly patients with chronic heart failure (CHF) age-related changes in the pharmacokinetics of fluvoxamine have been investigated [85]. As can be seen from Table 2, ageing resulted in considerable impairment of fluvoxamine disposition, whereas CHF caused no significant modifications. Likewise, in elderly patients twofold higher steady-state concentrations have been observed with other SSRIs such as citalopram, paroxetine and fluoxetine/norfluoxetine [86]. Based on the present evidence, in a minority of cases drug metabolism (hepatic CL) accomplished by the various CYP species can be slightly (up to 20 %) reduced with advancing age. In addition to the small impact of age several confounding factors will contribute to the observed variability of clinical studies. In general, phase II metabolism (e.g. glucuronidation, acetylation or sulfatation) is unaffected in the elderly [88, 89]. For this reason it will not be discussed in more detail. It can be concluded that age-related changes in drug metabolism are of minor clinical relevance.
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Fig. (5). Individual AUC values of diclofenac (top) and celecoxib (bottom) in healthy, genotyped (for CYP2C9) young (open columns) and elderly (solid columns) subjects (data from Brenner et al., 2003[82]).
Table 2.
Pharmacokinetic Parameters (Mean±SD) of Fluvoxamine (Single Oral Dose of 50 mg) in Young Subjects, Healthy Elderly Subjects and Elderly Patients with Chronic Heart Failure (CHF) (Data from Orlando et al., 2010[85]).
Pharmacokinetic Parameter
Young Subjects (Mean Age 35 Years) (n=10)
Elderly Subjects (Mean Age 73 Years) (n=10)
CHF Patients (Mean Age 79 Years) (n=10)
AUC (ng·h/mL)
304±84
885±560*
988±602†
CL/F (L/h/kg)
2.25±0.66
1.12±0.77***
0.88±0.41†
t1/2 (h)
12.9±6.4
21.2±6.2**
25.2±7.5†
Cmax (ng/mL)
15±3
31±19*
36±20†
tmax (h)
5(4-8)¶
4(2-8) ¶
4(2-8) † ¶
*P < 0.05; **P < 0.01; ***P < 0.001 vs. young subjects. † Non-significant (P > 0.05) vs. healthy elderly subjects. ¶ Median value (range).
Drug Transport It has been increasingly appreciated that membrane transporters play prominent roles in the processes of drug absorption, distribution, metabolism, and excretion [90, 91]. The best characterized drug transporter is P-gp, the product of the MDR1 gene, which has emerged as an important determinant of drug disposition in humans [92]. P-gp is highly expressed in intestinal epithelial cells, hepatocytes, and capillary endothelial cells, where it constitutes an essential barrier for xenobiotics [93, 94]. One ex vivo uptake study was conducted in leukocytes isolated from healthy elderly (n=18) frail (n=20) old subjects (age range, 68-80 years), and 21 young healthy subjects (mean age 33 years). The results indicated that ageing and frailty had only a minor impact on this validated cellular P-gp model and function of P-gp is apparently preserved in the elderly [95]. In 17 healthy volunteers (age range 18 to 86 years) cerebrovascular P-gp function was investigated using 11C-verapamil and posi-
tron emission tomography (PET). Older subjects showed significantly decreased P-gp function in internal capsule and corona radiata white matter and in orbitofrontal regions, which might explain part of the vulnerability of the ageing brain to white matter degeneration [96]. Therefore, an age-associated decline in P-gp function could facilitate the accumulation of toxic substances in the brain, thus increasing the risk of neurodegenerative pathology with ageing. Confounding Factors In the elderly frailty is of multifactorial origin and it is regarded as a fundamental risk factor for deteriorating health status and for disability. It is estimated that prevalence rates for frailty and prefrailty can be as high as 27% and 51%, respectively [97]. However, there is still no consensus on its definition or the criteria to identify frailty [98]. Frailty has already become an important issue and confounding factor when considering the impact of ageing on drug disposition [99]. Frailty was associated with higher inflammatory
Pharmacokinetic Changes in the Elderly
markers, such as C-reactive protein (CRP), interleukin-6 (IL-6) or tumour necrosis factor-alpha (TNF-alpha) and with a decline in metabolic activity of the aspirin esterases, a phase I enzyme [62]. In addition, in the elderly trauma and illness can also have substantial effects on plasma esterases [100, 101]. In the elderly also other factors such as pharmacogenetic polymorphisms [75], nutrition [87], comedications [57], smoking and drinking habits can influence the disposition of drugs. They should not be neglected but their detailed impact is outside the scope of this overview. EXCRETION With ageing, renal mass and the number of functioning glomeruli are decreasing by about 20-30%. After the age of 30 years, glomerular filtration rate (GFR) progressively declines at an average rate of 8 mL/min per decade, but one third of elderly persons show no decrease in renal function (GFR>70 mL/min/1.73 m2), and a small subpopulation has even an increase (P < 0.05) in creatinine CL with advancing age [102, 103]. Likewise, it was indicated that ageing per se had only a minor effect on kidney function. In the elderly, confounding factors, such as hypertension and chronic heart diseases, account for a decline in kidney function [104, 105]. In addition, the Italian Longitudinal Study on Ageing (ILSA) demonstrated that in elderly subjects an age-associated reduction of renal function was associated with coexisting cardiovascular diseases and other risk factors [106]. Furthermore, one recent report compared purely age-related changes of pharmacokinetic parameters for 127 drugs. The overall analysis revealed an age-related prolongation of t1/2 of 39±61% (mean ±SD); contrasting to the general opinion, CL (-1±54%) was hardly decreased whereas V (+24±56%) was slightly increased and probably caused the increase in t1/2. The modest changes in pharmacokinetics do not suggest general dosage modifications in the elderly for most drugs [18]. Thus, in the absence of diseases, GFR may not decrease as greatly as previously thought. Serum creatinine is a commonly used measure of kidney function, but in the elderly serum creatinine levels appear to be influenced by factors other than kidney function and muscle mass [107]. As a consequence, in the elderly serum creatinine is not an adequate indicator of renal function. Due to reduced muscle mass, older subjects frequently have a decline in GFR despite normal serum creatinine, and such “masked” renal insufficiency may alter significantly the CL of polar drugs [19, 108]. Measuring GFR is widely accepted as the best overall index of kidney function. GFR can be estimated by empiric equations. The two most commonly used formulas are the Cockcroft-Gault equation and the “Modification of Diet in Renal Disease” (MDRD) formula [109, 110]. Because in the elderly the Cockcroft-Gault equation systematically underestimates GFR, GFR should be estimated applying the MDRD formula [110, 111]. In a retrospective study of 154 elderly patients ( 65 years) registered to receive home healthcare, 14% of hospital admissions were primarily caused by ADRs and one-third of these ADRs were related to impaired renal function calculated by the MDRD formula [112]. In 2009, a more accurate GFR assessment, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, was introduced [113]. The CKD-EPI method performed even better than the MDRD equation, especially at higher GFR (>60 mL/min/1.73 m2), with less bias and greater accuracy [114]. In addition, serum cystatin C should be superior to serum creatinine for the calculation of GFR because it is less affected by extrarenal factors [115-117]. Whether the minor age-dependent changes in renal function are of clinical relevance will depend on the extent of renal elimination contributing to total systemic elimination and on the therapeutic index of the individual drug. Anticipated changes in renal function might affect the renal elimination and action of some drugs with a
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narrow therapeutic index, such as lithium [118], digoxin [46], and aminoglycosides [48]. More recently, some studies reported age-related difference in pharmacokinetics [119-121], while others found no significant changes [122, 123]. In elderly subjects CL/F of lecozotan was approximately 35% lower in elderly subjects (27.5 mL/h/kg) in comparison with young subjects (42.4 mL/h/kg). Consequently, after multiple dosing mean t1/2 in elderly subjects was 11 h, which is slightly longer than mean t1/2 of 7 h in young subjects [119]. It has been indicated that CL/F of most old and new generation antiepileptic drugs was reduced on average by about 20 to 40% in elderly patients if compared to nonelderly adults, which can be ascribed to a reduction in the rate of drug metabolism, of renal excretion, or to both [120, 121]. In the elderly, the interindividual pharmacokinetic variability is particularly prominent.However it is due not only to the influence of age-related physiological changes, but also to the impact of comorbidities and drug interactions. CONCLUSIONS The proportion of elderly populations is increasing constantly. This will cause various problems to our health care system. Physiologic changes and disease-related alterations in organ function occur with ageing and can affect pharmacokinetics. Comorbidity, polypharmacy, frailty, and disability may occur and will complicate drug therapy. In addition, in the elderly non-adherence to drug regimens and inappropriate prescribing are of great concern, and both might be a major cause of ADRs and drug interactions [124, 125]. Thus, providing safe and effective drug treatment in older patients is a great and arduous task. Presently, in the elderly a few minor and variable changes in some pharmacokinetic properties of certain drugs are likely to occur, which can be summarized as follows: (a) a decrease of bioavailability of some drugs when active transport mechanisms are involved; (b) an increase of bioavailability of some high-CL drugs undergoing extensive first-pass metabolism; (c) an increase of V (and t1/2) of lipophilic drugs; (d) CYP enzyme activity is preserved in normal ageing; (e) although in vitro data indicate no significant impairments in drug metabolism and the involved enzyme activities, hepatic CL can be slightly decreased (approximately 20 %) in some cases; (f) the genetic influence on metabolism is much more striking than age effects; (g) renal CL is less impaired than previously thought; (h) the interindividual variability in drug disposition is particularly prominent in the elderly probably due to several confounding factors (e.g. comorbidity, polypharmacy, drug interactions). Although it has been recognized for a long time that the elderly display a number of metabolic and pharmacokinetic changes, clinical trials are commonly carried out either in healthy volunteers or carefully selected patients. Thus, there is an urgent need to generate more clinical data for the increasing elderly population that consumes a more than proportionate share of all drugs. Conventionally, the “elderly” has been defined most frequently by a chronological age of 65 years and older because there are as yet no biological age markers. Furthermore, dividing the elderly into three age subgroups (as done in pediatrics), such as 65–75, 76–85, and above 85 years, might be helpful in a better understanding of the various ageing processes. In addition, a clear differentiation between the fit elderly (to study the impact of ageing) and the frail elderly (to assess the clinical reality) would be useful. It has been generally accepted that metabolizing enzymes and drug transporters, acting alone or in concert with each other, will affect the pharmacokinetics of a drug [52, 53, 126]. In the future, their function, pharmacology and “interplay” should be carefully examined for age-related effects. Importantly, when performing pharmacokinetic studies in the elderly, age-related changes in the pharmacodynamics should be also assessed and monitored. Subsequently, drug dosing should be adjusted to both, changes in pharmacokinetics and pharmacody-
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namics. Based on the limited available information on the impact of ageing for pharmacokinetic properties, no distinct and definite dosage guidelines can be given. The complexity of the interactions between comorbidity, polypharmacy, changes in pharmacodynamic sensitivity and modest pharmacokinetic changes in the elderly suggest to follow the old and well-known slogan "start low, go slow" for aged individuals. ACKNOWLEDGEMENTS This work was supported by the the Natural Science Foundation of Hubei Province (No. 2009CDB380), PR China and Robert Bosch Foundation Stuttgart, Germany.
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CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.
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Received: September 13, 2010
Revised: December 8, 2010
Accepted: December 8, 2010
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