27:e American Jor~rnaI oFGeriarHc Pbarmacor::erapy
B ~ Cu fack
Pharmacokinetics in Older Persons
Barry J. Cusack, MD
Ce~,n oio'vy ~ nd Pha,cr,: coio~y ~e:.ecach LJn ~. 7?\ ,'~,"e41cci Cente!, n d A/oun cin ~tc,:es ~:~:,o~- .,nd :Vedic'~ i %sec r h
Ins~tu~e, Boise, l&ho, :.end DJzson of Ce©n olcgy c,nd Ce& tr.c MedJene, School c,IMedJcir,.e, (JnJvemh,v of I~/cshng,'on,
5eottie. Yl/~'sh ngton
ABSTRACT
Background: Physiologic changes arid disease related altea'aEons in organ function occm' with aging. These changes
can affect drng pharmacokineEcs in older persons.
Objective: TIEs axEcle reviews age related changes in pharmacokineEcs and their clinical relevance.
Melhods: A PnbMed search was conducted using the terms eMerlyand pk~f~c~cok@~e~ics. Other reviews were also
included for literature searcbdng, The review includes literature in paxtic~ax from 1990 through April 2004. Some
articles fiom bdbre 1990 were included m help illustrate principles of age related pharmacokinetics.
l{esuhs: There axe minor changes in drug absorption with a~dng. The effect of aging on small bowel transporter
systems is not yet fully established. Bioavailability of highly extracted drugs often is increased with age. Transdermal
absorption may be delayed, especially in the case of water soluble compounds. Fat soluble drugs may distribute
more widely and water soluble drugs less extensively in older persons. Hepatic drug metabolism shows xdde
interindividnal vaxiation, arid in many cases, there is an age related decline in elimination of metabolized drugs, par
ticnlaxly those din'dnated by die cytocfuome enzyme system. Any decrenrent in cytod~ome enzyme metabolisnr
appeaxs nonselective. Synthetic conjugation nietabolism is less affected by age. Pseudocapillarizadon of the sinn
soidal endotbelinm in the liver, restricting oxTgen diffusion, and the decline in liver size and liver blood flow may
influence age tdated changes in rate of hepatic metabolism. Frailty, physiological stress, and illness are important
predictors of drug metabolism in older indi~ddnals. Inhibition of drug metabolism is not altered wifll aging, but
induction is reduced in a m5nority of studies. Renal drug elimination typically declines with age, commensurate ~4th
the fall in aeatinine cleaxance. Renal tubnlax orgaxlic acid transport may decline w-ifll age, while tim function of the
orgarEc base transporter is preserved but nray be less responsive to stimalaEon.
Conclusion: Changes in pharmacokineEcs occt~ due m age related physiologic pertnrbadons. These chaxlges
contribute to altered dose requirements in older persons, particulaxly in the case of &rigs eliminated by the kidney.
Interindividnal variation, disease, ffailt}; arid st*ess may overshadow age related changes. (A*~ J Geri~tr Pkc~f'~
cotkee: 2004;2:274 302) Copyright tc? 2004 Excerpta Medica, Inc.
Key words: pharmacokinerics, metabolism, aging, older persons, elderly,
Accepted t~, publicotion october 22, 2004
Printed in the USA Rep:oductior~ in whole or part is uot permitted
274
Decs~zbcr
2004
v o l u m e 2 * iXur %er 4
doi:lOiOio/j
r,opharrn2OCd i2005
1543 5946/04151900
CopyrigJ~ {© 2004 bxcerpts Nedica h~c
B 5 Cu ;r~ck
iNTRODUCTION
Pharmacotherapy of older patients is faced widl ma W
challenges. Age related changes in physiolo~7 and organ
function alter drug handling (pharmacokinetics) and
response (pharmacodynaufics). Multiple diseases a*e
more common in advarlced age aud affect drug disposi
tiou a*ld tesponse by a magrfitude related m disease sever
it}'. In additiou, older persons take more medications in
"eeatiug multiple disorders, increasing the risk o f
drug drug and drug disease interactions. These concerns
need to be considered when t~eatiug older patients.
hi dlis a*ticle, the effect of age on pharnlacokinetics
and its clinical relevance will be texdewed. HoweveG it
is clear dlat pharniacokinetics is ouly one o f m a W fac
tors that influence decisious tega*ding drug therapy in
older patients.
MATERIALS A N D M E T H O D S
The PubMed database was semched using the terms
elderly and phc~r*,~co/eine~ic~ in tile article titles. This was
judged m be the most e~bctive metllod of obtaining r d e
vant articles. &ticles in £ngiish from die beginniug of
1990 m April 2004 were selected. A total o f 252 arti
des were obtained. £xamanation of these and of other
reviews led to further sot~ce references. N o t all the r e f
erences were included; emphasis was placed ou drugs
that ate mote relevant m clinical practice and on articles
that best illustrate pha*macokinetics priuciples germane
to the aging process. In some cases, importaut studies
from before 1990 have been included to help deniou
sttate pharmacokinetic ptiuciples. Readers interested in
more extensive analysis ofpharmacokinetics a*e referred
to several excellent reviews, q ql In addition, readers a*e
reffetred m more recent general reviews for supplemen
ted informatiou, q2 z9 Throughout die text, the terms
younger c~dult or young ~dult are used and typically refer
to adults <40 yeats of age. The terms elderly or older
persons D~ically denote those aged >65 yea*s.
Pharmacokinetics refers m the process of & u g hau
dling by the tissue, orgau, ot body. Pa*ameters that ate
typically included are absorption, bioavallabilit}~, distd
button, metabolism, and excretion. These pa*ameters
can be altered in older persons, not only due m aging
but also by disease and & u g effects. In dtis v d n , the r d
ative conts'ibutious o f age or other parameters ate dis
cussed here. [n addition, the t dative cliifical importance
of'age tdated changes in pha*macokiuetics is described.
ABSORPTION
D r u g absorption is mair~iy a passive process. Most
drugs a*e absorbed in the s m a f bowel. The extent o f
Th~ Americ~ez Joe*r#¢MqFGeriatric Ph~rm~co~her~
absorption depends ou ttle absorptive capacity of the
s m a f bowel, wtfich shows little chauge x~4th agiug. To
assess the extent o f absorption, a coniparison is made
between the A U C after oral and IV adminisrzatiom In
die last decade, few studies have examined the extent o f
absorption. Those studies that have been conducted
corroborate the pt evatling opirtion that agiug does not
affect die extent o f absorption (Xable I .~ °*
The rate of absorption is a more commouly mea
sated pa*ametet since it requites estimation of plasma
drug concenuatiou cmly after oral dosing. It typi< ally is
denoted by Tm~ : ot the first order rate constant. The
rate of absorption depends to a degree ou the rate o f
gastric emptying. Using acetaminophen as a probe,
Gainsborough et al ~ carefvflly examined the rate o f
d r a g absorption as an indirect index of gastzic empty
ing in 19 healthy youug (mean age, 25 years; range,
20 33 yea*s) arid 19 healdly older (meau age, 75 yeats;
range, 69 86 years) voluuteets. The results showed no
signifcant difference in auy o f the derived parameters
~;Jt rate ofabsotptiou between the 2 groups. This sug
gests that aging does riot impart this rate limiting step
o f gastric e m p t ~ n g in & u g absorption. Howeve h the
;ate o f absorption is not o f significant impot ta*rce from
a cliulcal perspective, with the exception o f certain
drugs that require a rapid onset o f action, such as anal
gesics and hypnotics.
Presystemic extraction in the bowd mucosa and in die
liver may sigrfificantly alter bioavallabili V of some drugs.
Such drugs haze a high ext,'action ratio iu die liver (vpi
tally >70%), and tiffs limits bioavailabili V o f such & u g s
to -~30%. Studies have shown that the bioavallability of
lidocalne, 34 verapantil, 37 and labetalol ~a is increased in
older persons arid is tdated to decreased hepatic extrac
tion on ~ s t pass through the liver.
gioavallability may also be regulated by presystenfic
extraction by small bowel cytodKome P 450 (CYP) 3A4
activit~ and by the extzusive action of Pglycoptotein
(P gp), the efflux transporter located on tile apical sin'
e~ces of" superficial columua* epidlelial ceils of the small
bowel and other tissues. Study o f human liver and ptoxi
mar small bowel specimens iu surgery patients tevealed a
much higher coutent o f both CYP3A4 protein and
P g p in euterocytes isolated from human duodenal or
jejunal mucosa than in paired specimens o fir\ er txssue.The t?dgh content o f P gp on the apical s ~ face ofentero
cytes supports the tileory that d~is efflnx tzausporter
may act iu concert with C\~23A4 to limit oral drug
bioavallabili w. Limited data do riot support an effect
o f aging on either process. The bioavailabili w o f
cyclospodne, a substzate fbr CYP3A4, was uot affected
27S
27Jr A~ericaez Jonr~¢M of GeriarJic PbarfezacoffJerapy
B 5 Cufach
Table I. Effect of aging on drug absorption (following oral administration, unless stated otherwise).
DI" Llg
V 'l
,(J
>
No dF'srer~ce
Bumetunide
Cephradire
~O rr!rrl@rlt
94%
¢,eP~: ence
Oberbauer et aiso
94%
Schwinghar!!!ner et ai'q
Ciprofioxscin
63%
79%
I jungbe!g and l'qiisson Fhie~
CoicHcine
44%
45%
Rochdi et :A'3
Fentar,;,i
C:,~.~ and ] m~
ur affected
FlucloxaciHin
Indot nethacin
54°6
i 00%
/736
Porn 50 .g/h
lhompson et ai;4
transdermai pa±ch
l'qo dP( ter!ce
$
GaSh et aP's
OberbaueF et ai/6
Kctanserin
$ b7 60% in eide!i 7
Gould et aY'
Ondar!seVotq
Bioavaiiabii%, not
significanti/ o anged
Pric(J-!ard et ai?
Nc%cioprardde
"Jncl-~anged
',/'6/nr e eL al>
~8%
%%
oiutior
u s b i n e d release
Baiiiie eL aJs°
Norphine
36%
37%
Monteluk~st
6?%
oi%
blistoricaJ /oung group
7hao et a131
Nalbupisine
i7%
46%
~
]aiiion et aiss
Repaglinide
~lithl-omy,zuq
%
C
ar d i,;.×
ur!Jfectcd
579"
57%
Perlet et als4
percentdge oF drug dose gi,,en; ? = £atbdcally significant ina ease; $ = <latis÷ically significant decrease
by age in a group of ~ensdc patients. 4J Grapefruit juice,
a known inifibitor o f intestinal CYP3A protein expres
•
41
slon,
~ enhanced the bioavailability of fklodipine in
elderly (aged 70 83 yeas) indi;{duals wit)~ a 2.9 fbld
increase in mean A U C and a 4 told increase in C .4~
T N s suggests that presystemic CYP3A4 activity remains
important in limiting the bioavallability of substrates
such as ~e[odipine into old age.
The idea that aging alters the role of enteral P g p
activity arid dlereby alters bioavailability was explored
using fexof;madine, a known substrate for P gp/*~
Fexofenadine was admiuistered to 12 young (age raige,
22 35 y e a s ) arid 12 older (age range, 65 76 years)
healthy male a i d female volunteers before arid after
treatment with 600 m g oral ri~ampin tbr 6 days. The
oral clearance of fexofenadiue was not affhcted by age or
sex. However, rifampin, an inducer of CYP3A4 as well
as an upregulator of P gp, markedly increased the oral
clea'ance o f fexotknadine in all groups. Since the
CYP3A4 mediated, dealkylated metabolite azacyclonol
276
Hatorp et a P
constituted a very low fraction (0.5%) of total drug
given, it was concluded that activation o f CYP3A4
played a tuidimal role in c h a u ~ n g die oral cleaance of
fFxofenadine. Thus, the deternfinant of'increased oral
clea'ance due to rifampin was considered to be reduced
oral bioavailability due to induction of P gp mediated
excretory intestinal transport. The authors concluded
that age did not alter P g p activity arid that P g p activ
ity was similaly induced by tifampin rega'dless of age.
Interpretation of" these dam is fm'thet complicated by
information from subsequent studies by Dresser et al,44
which demonstrated that [hxofhnadine is also a substrate
fbr the bowel mucosal organic anion transporting
polypeptides (OATPs) d~at f~cilitate mucosal drug
uptake arid ate inhibited by juices such as g~apefruit
juice, thereby deaeasing oral fexofbnadiue bioavailabil
itv. They also perfbrmed in vitro studies sho~@ig that
gtape~uit juice inhibited OATPs rather d~an P gp. [n
aggregate, these data suggest that fexofenadine bioavail
ability may be more dependent on OATPs than on
B~ Cufc¢ck
'dcuJa~ benefit in older patients. Percutaneous absorp
P g p . Clearly, further study is needed to determine the
el'tinct of aging on these influx and effit~x transporters.
Absorption of medications also depends on their
physicochemical characteris'dcs and on bowel milieu. For
example, phenymin is water insoluble and needs an alka
line environment and sufficient water for adequate disso
In'don to permit absorption. 4~ In a stud)" of steady state
concenu'a'dons of phenymin in 56 elderly uuxsing home
pa'den~s who had ~3 serial measuremeu~s, pheuytoin
concentta'dons (Figure 1) showed marked variability
w-ffhin individuals on a consistent dose of drug, 46 The
autho*s ascribed this int~aludi\~dual variability m changes
in absorp'don tdated to variable find intake and bowel
transit time among residents, While this explaua'don may
not be correct, since very large variafions in fluid intake
would be necessary to significantly alter phenytoin disso
lu'don, there is no od~er obvious explana'don. In any
event, the varia'don iu drug concentta'dons is dramatic
and a sobering reminder that single es'dmations of drug
coucentta'don or single dose pharmacokine'dcs studies
may not be predic'dve of steady state concentrations in
frail elderly patients. This intriguing observa'don requires
further corroboration and analysis.
Transdermal drug administ~a'don has become an
increasingly important method of dr ug delivery of p a
35 l
'don requires not only diffusion of drug across the stsa
t a m corneum, but also uptake by the tNcrocircula'don
~{th delivery to t&e systemic circulatiom There are
many changes in skin morphology and func'don that
can alter percutaneous drug p e n e u ' a t i o u S These
include drying of the stratum corneum, changes in
sebaceous gland ac'dvity and lipid composition in the
skin smface layers, and flattening of the dermoepider
real junction with a decrease in the number of dermal
capillasy loops. Systematic inves'dgation by Koskos et
al4~ using radiolabeled compouuds and by combining
surface recovery methods with 74C minary drug recov
ery, showed a variable effect of age on transdermal
transport, depending on the physicochemical proper
'des of the drug. Thus, the more lipophilic corn
poundsMncluding testosterone and es~radiol were
less well absorbed, ~ t h greater skin recovery and ~ t h
no age difference in absorp'dom Conversely, more
hydrophilic compounds including benzoic acid,
ace@salicylic acid, and caffeine were better absorbed,
~;ith less dermal recovery, and absorption was g~eater
in young subjects compared vdtt~ older subjects. In
another study ofttansdermal f'entanyl pharmacokiue'dcs
in postoperative pa'denLs, plasma fbnta@ concenu'a
Aged 65-74 years
(n = 18)
i
The Americ~ez fo~r~eM of'Geriatric ~Ph~rma~cofl~er~ey
Aged 7 5 4 4 years
(n = 21)
Aged ->85 years
(n = 17)
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Figure I, Individual total plasma phenytoin concentrations in elderly nursing home residents, Each symbol (x) represents a
single measurement, and the vertical lines connect all concentration estimations within each individual. Squares represent drug levels observed after phenytoin was given via a gastric tube. The "therapeutic range" for phenytoin is
marked by solid horizontal lines at 10 and 20 pg/mL. Reprinted with permission. 46
277
2}e American/o~rnd oflGeriar~ic Pharmacor;¢erapy
B5 Cu;ack
yeats) adult volunteers. 4~' Absorption parameters were
similar in both groups, suggesting ti~at tiffs route of
absorption remains preserved into older age.
tions were measmed using radioimmunoassa 7 in blood
samples obtained during patch application for 72 hours
and for 30 horns after patch removal. 24 The mean h N f
time (time fiot plasma concentrations to double after
patch application) was 4 2 horns in the younger gr'oup
and 11.1 horns in the elderly group ( ? < 0.005).
However, the mean C
values were 1.9 n g / m L and
1.5 n g / m L in the younger and elderly groups, respec
tively (P > 0.05). There were no diff~retlces in the d i m
ination hal~life after patch removal ot in the A U C to
infinity (Figure 2). Thus, ~vith increasing age, there
may be a greater battier to drug absorption, especially
for water soluble compounds, and the rate o f absotp
don may be delayed. The number o f studies that have
specifically exat~iued the effect of aging on percuta
neons drug delivery is small, however, and does not
permit definitive conclusions.
Some dr ugs are now adnirffstered via the oral mucosa,
permitting mote rapid absorption and deateased first
pass metabolism compared wlti~ the s~allowed drug
given orallF: This mode of delivery is particularly benefi
cial in tire t~eauneut of pain in cancer patients who need
rapid relief of breakthrough pain. Fentat~yl is used For
such proposes. The eff?ct of age on ti~e oral t~ansmu
cosal absorption of fEntanyl has been assessed in F~ung
(age range, 18 40 years) and older (age range, 6 0 ~ 5
DRUG
DISTRII-~IUTION
Afte~ absorption, drugs disttibnte tt~ough the body,
and tile extent of distribution t dative to the amount of
drug iu the plasma is termed the volume o f distribution
(Vd). Vd does not tefe~ to a W physiological volume: it
defines the rdationship between plasma ot serum drug
concentrations and the amount o f drug in the bodF~ It
is expressed as:
A m o u n t o f drug in body (mass)
plasma drug concentration X Vd
Vd is high if tile plasma content o f drug is low rela
tive to the amount o f drug that has distributed to ti~e
exriavasc ular space. Convet selG if the plasma content of
drug is ~elatively high compated with the exu'avascular
fraction, then the Vd is low. D~ug factors that can aft:ect
Vd include partition coefficients, ionization state, and
a~fiulty flot various body tissues. Many other factors dic
rate Vd, including body size, sex, body composition
(leg, Fat content), and disease state. Aging can aff?ct Vd
because of relative changes in body h t ti~at increase
A ¥oungadult patients
J Elderly patients
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Figure 2, Mean (SEN) plasma fentanyl concentrations after transdermal fentanyl patch placement in young adult (25-38
years) and elderly (64-82 years) patients,The patches were removed at 72 hours, Reprinted with permission. 24
278
B ~ Cufr¢ck
with age and changes in lean body mass that decrease
with age5 ° ~2 Thus, drugs such as chlotdiazepoxide,
diazepam, lidocaine, oxazepam, and chlom~etbiazole
that me fat soluble are taken up into fatty tissue arid
have a rdatively increased Vd in older persons, as
reviewed by Dmnas et al4 In couUast, drugs such as
sotalol, ~3 antipytine, ~4 and ethanol, ~< which a*e water
soluble, are confined more to lean body tissues and
have a decreased Vd in older persons,
Age related changes in Vd can have signiEcant dire
cal implications, Vd is related to clearance (CI) and
hal~lif~ (t~/2) as follows:
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Vd = C[ X t:Lr,2/0,693
Thus, Vd can affect the dinaination halglife. For
example, in older persons, Vd o f diazepam is elevated
(Figure 3), and although the systemic clearance is
unchanged, the elinlinaffon half'life is markedly pro
longed, ~6 potentially prolonging the dusatiou o f action
o f the drug. These data also serve as an explicit
reminder that an increase in elimination hal5life o f a
drug may be due to altered Vd arid does riot necessa~
ily imply a reduced rate o f elimination.
Because Vd is a deteruinant o f the plasma concenUa
"don vdtb acute dosing, it is a major determinant of the
loading dose o f a drug in the body. Thus, the loading
dose of digoxin is decreased in older individuals based
on the lower Vd, an effect likely related to decreased
muscle mass57 Acute doses o f ethanol produce higher
plasma concenuations in older individuals, related at
least in p a t to a decreased Vd, ~ prmdding a rationale
for additional caution regarding driving in older persons
with already impaired ueuromotor function7%
Drugs circulating in plasma bind to a variable debt ee
to protein. Acidic drugs bind to albumin whereas basic
drugs bind to alpha± acid glycoprotein. Changes in
binding of drugs flint are extensively bound (>90%)
cause significant changes in free drug concentration.
There are sigmficant, albeit small changes in serum
albumin concentrations with aging, so fllat binding o f
some drugs (eg, vulproate, diflunisal, salicylate,
naproxen, acetazolan'dde) is decreased, resttlting in
increased flee drug concentrations in older p e r s o n s #
The changes that occur in healthy elderly persons a*e
small and not important clinically. However, elderly
patients often have significant declines in albunfin lev
els such as occurs x~4th severe acute illness, in postoper
ative states, arid ,s4th malnutrition associated ~4th
hypercatabolic stares, resulting in elevations o f flee
drug levds, although the total concentxations may be
The Americ~ez fof~r~¢~[ of Geriatric Ph~rma~coff~er~ey
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Figure 3 Relationship between age and diazepam (A) elimination half-life, (B) volume of distribution, and
(C) total plasma clearance in healthy volunteers,
Adapted with permission, s6
279
27~eAmerican Joe*rnM o~ Geria~Hc Pgarmaco~;~erapy
B ~< Cuba&
decreased. In such circumstances, it is preferable, when
possible, to measure flee drug concentxaEons since
total drug concentrations can be misleading.
The levels o f alpha s acid giycoprotein increase
slightly ~ t h age in healtily individuals, and the difi~r
ence w-ifl~ age is less in those x~4fl~ inflammauon. 6°
Some drugs such as prazosin 6s show no significant
change, but lidocaine (lignocaine) binding increases
w-ith age. s6 In the latter study, maximum binding
capacity of lidocaine (lignocaine) was greater in the
elderly, but the biading ai'finity did not significantly
change with age, consistent w-ifl~ increased concenu'a
don of the binding protein. With acute ifiness, tiffs pro
tein concentration increases, resulting in higher total
plasma levels o f bound basic drug. Therefore, increased
lidocaine concentrations in the plasma ai'ter an acute
myocardial ini:a~ction may represent g~eatet binding m
alpha s acid giycoptoteln. ~* Thus, binding o f some
basic drugs nmy be increased in older persons, but
acute ifiness may have a much more profound ei'fhct.
It is not yet known whether there are age related
changes in P g p , an adenosine triphosphate dependent
cell membrane pump that can ext~ ude xenobiotics from
"din cell. This could affect drug distribution to the
brain, absorption o f drugs from the small bowel, and
elimination o f drug fiom the bilim'y system and renal
tnbttles, which are sites o f highest concenuations o f
P g p . In the Fischer 344 rat, the effect o f age on P g p
expression was tissue specific. Although lymphocytic
and hepatic P g p expression increased ,~ith age, renal
P g p content was lower in kidneys from senescent rats
compared wiflx younger adult rats. 6~
D R U G METABOLISM
Recent reviews have very capably outlined the role of
aging in determining the {'ate o f drug metabolism,
which occurs mainly in the live*' arid which oi:Len is
reduced with advancing age. s<x4,64 The reasons why
drug metabolism may be reduced ~fl~ age have uot
been satis~hcmrily elucidated. There are minimal qnan
tirative changes in liver function and in liver histol
ogg~, although liver size and blood flow decrease with
aging. ~<65 Classic studies by l<ato and Takanaka, 6<6r
observing that fl~e in vitro content o f CYP, N A D P H
cymchrome c rednctase, and in vivo rates of drug
metabolism declined with age in rats, led to cfi~fical
investigations. Two broad clinical questions wea'e rele
vant: (1) Did the principal drug metabolizing cyto
chrome enzyme system change ~a4th aging? and
(2) Was drug metabolism in sdvo age dependent? The
most comprehensive investigation of the d'fEct of aging
280
on the content o f liver microsomal monooxygenases
was performed maiuly in healthy donor tissue by
Schmucker et al.6~ They obtained tissue from 54 liver
samples from individuals aged 9 to 89 year's for assay of
the content o f microsomal protein and CYP, as well as
the activity o f N A D P H c y t o d x o m e c redncmse. They
did not find any change with age in e n ~ m e content or
activity. A different approach was taken by Sotaniemi et
ale,9 who studied CYP content and antipyfine clearance
in 226 individuals who had a liver biopsy and clinical
evaluation. These individuals had equivalent slight to
moderate hepatic tEstopafl~ologic changes. There was a
significant decrease in CYP content and in antipyfine
clearance in those aged >70 years compazed ~4th young
adults. The study suggested an age related change in
chug metabolism, ~dti~ the caveat that all o f the indi
~idnals were undergoing liver biopsy ~or diagnostic
purposes and had minor, albdt equivalent histopatho
logic abnormalities.
A logical extension o f these studies is m exanfine
whefl~er there is any difference in the effiect of age on
the content or activity o f individual cymctu'ome isoen
z3/mes in humans. This was addressed by St~mada et
alto who studied in vitto en©~me metabolism fiom liver
samples from 30 white and 30 Japanese individuals. The
CYP enzymes in tiffs study included 1A2, 2A6, 2B6,
2C, 2D6, 2 E l , and 3A, and monooxTgenase activ
ides were determined using 113 ~pical CYP snbst~ates
and 9 procm'cinogens. They could not detect a W appar
ent changes in CYP content and activity in humans
between 12 and 73 years o f age. Thus, while this study
was funited to some degtee in size and did not contain
tissue from very old individuals, it does not support any
age related change in cytochiome isoenzyme activity.
Given the eflEcal and logistical considerations in per
fbrming studies o f this nature, ~ t h inclusion o f healthy
dderly subjects, it is nulikely timt any larger studies ~ l l
be perfiormed to address this question.
The discrepancy between findings of reduced drug
metaboEsm, especially of oxTgen dependent metabo
lism, in older persons and a lack of" change in drug
metabolizing enzyme content or activity leads m alterna
tire explanations. A novel hypofllesis has been proposed
by Le Conteur and Mclean 7s from Sydney, Australia, m
e~plain this dichotomy, namdy that aging is assodated
with hepatic sinnsoid psendocapillarization flint leads to
*'educed diffusion and decreased drug metabolism. T h d r
studies in tim Fischer 344 rat have demonsu'ated age
*'elated psendocapillariTation of the sinnsoidal endothe
Enm in the fiver, indicated by deFcnestt ation v~4th reduced
porosity, fl'dckerEng of the endofl~dinm, and infrequent
development of basal lwnina. 72 In addition, immuno
ttistochemistry studies showed significant changes in
expression of collagen (P < 0.001). In vitro Sip magnetic
resonance spectroscopy analysis showed dmt aging is
associated ,a~d~ changes in high energy phosphate and
other metabolites, consistent with hepatocyte hypoxia72
Thus, aging is assodated ~,vittl changes in the sinusoidal
endothdimn that may tesuict the availability of oxygen
and other substxates For drug metabolism. Furthermore,
oxidative stxess (a purported niechanism of aging),
induced in the perfhsed rat liver w-id~ hy&ogen pet oxide,
caused a 14% + 9% (P 0.03) reduction in oxygen uptake
and a decrease in the intrinsic clearance of ptopranolol
(phase 1 oxidative metabolism) greater thwl tflar of mor
ptffne (phise 2 corrugation metaboffsm) o f 57% + 14%
versus 34% + 7% (P < 0.005)7 s These data support the
concept of a restxiction of oxTgen supply constrair~ng
hepatic dr ug metabolism, mainly oxidative drug metabo
lisa. [mportand}; pseudocapillarization in the INer also
has been demonsnated x~4dl aging in the baboon % arid
other spedes, including humans 7~
The setulnal cliedcal study of in vivo drug metabolism
by O'Malley et al76 demonstrated that elimination half
lives o f antipyrine, a classical probe for in vivo drug
metabolism, were prolonged in elderly subjects.
Antipyrine is a good choice as a nonspecific probe o f
hepatic phase 1 drug metabolism in that it is not highly
protein bound, its elimination is capacity limited, wld
it is almost completdy metabolized by the CYP system,
being a substrate for at least 6 enzymes, including
CYP3A4, 1A2, 2B6, 2C18, and others77 Fm'ther stud
ies in >300 individuals from the Baltimore Longi
tndinal Study of Aging demonstsated dlat alttlongh
aging influenced the elimination of" antipydne, there
was considerable interindividual vwiation in the rate o f
elirrination, o f which ouly 3% was explained by age. 78
Smoking also influenced the rate of antipydne elimffna
"don and could be a confounding factor in studies o f
aging arid drug metabolism. %,7> Thus, from studies o f
antipydne alone, a number of'important observations
were made. While the rate o f drug metabolism was age
rdated, confbunding factors such as cigarette smoking
influenced the appwent age effect, and the overall
importance o f age was riot very high.
Given the variability of hepatic drug biotransfotma
"don, it is also important to have larger numbers ofindi
viduals in the study to acquire more representative
data, as in the study by Vestal et al78 Many o f the
studies over the last ~-10 years, as given in Table
ii23,2~8,8!,88,80 142 w~d pdor studies 4 me relatively
small, typically including <20 individuals in each age
group. This may explain, in pwt, why the majority o f
studies do not demonstrate an age difference in the rate
o f hepatic drug elinfination. This may also be a reason
for the variation between diffbrent studies o f individual
drugs. Thus, in interpreting these data, it is more
important to seek tsends that a number of investiga
tions suggest tattmr than attribute a high level of evi
dence to any one study.
Neatly all the studies on phwmacokinetics and aging
are cross sectional in design, compwing individuals o f
different ages. It is possible ttlat any alleged age differ
erlce might be due to generational cohort differences
rather than the effect o f aging per se. Longimdinal
studies are requited to ascertain true effects of aging.
Due m expense arid time requirements, prospective
longitudinal studies o f this nature have not been pet
fbtmed. Another approach was taken by Wynne et al±4s
in Newcastle, United Kingdom, who retrospectively
reviewed warfwin dose requirements in a group o f
patients who had been t~eated for 6 to 24 yews.
Sensiti~i w to warfarin did not change significantly ~vith
age. ~Varfadn requirements f~ll over time, and the
dosage difference was signiflcandy corrdated with the
age diff~erence (P 0.01, r 0.25). Regression wlalysis
deteHrdned that there was a 21% decrease in warfffrin
requirements in this population over a 15 yew period.
These results are compatible with a longitudinal age
related decline in warfarin requirements and we consis
tent ~ t h other cross sectional studies o f warfarin
pharmacokinetics, sensitiviD; and aging. 144,14~
The effect of" aging on drug elimination by individ
ual cymct~ome i s o e n ~ m e s is difficult to exanfine in
ma W cases since an individual drug may be a subsuate
fbr >1 enzyme. Nevertheless, recent reviews of tfle lit
eramre by several authors ptoxfde some appreciation o f
the age dependence o f individual pathways. ~s,±4j8
Based on these reviews, it appears that the rate ofelimi
nation may be decreased for substsates o f CYP1A2 and
2C19, decreased or unchanged fbr subst~ates o f
CYP3A4, 2A, and 2C9, and unchanged ffor substrates
o f CYP2D6. Thus, there is variation in the efthct o f
aging on clearance o f drugs that are sabst~ates fbr indi
vidual CYP isoenz3mes , both between and ~a~thin
isoenzyme classes. O n e interesting noninvasive
approach to determine the rate o f metabolism o f an
individual pad~way is the use o f the [ 14C]erytt~omycin
breath test as performed by H u n t et all46 In human
liver nticrosomes, the giucocorticoid inducible CYP3A
isoenzyme catalyzes the N demethylation of eryd~o
rwcin. In their study, die rate of erythromycin N
demethylation was examined, as reflected by the
2111
T}~eAmerican ~¢~r,~r~caI o~Geria~ ic Pbarma~o~;~era~y
B~ Cu ~a~k
Table II. Effect of aging on hepatic drug metabolism.
Dlu8
~5ur ~{
Elder b
CofYirr 18[it
£,eP~]rer ice
AUC, 5216
ng/mL per hour~
Old (r~,ean ace,
83 years}
nouva± et al °
Pegvlat ~d ints~uron
Cl/b 8(, ~t%
Aces l 0 80 years
Gupta et ;d8!
alf~ 2',
of young
Diltiazerq SR
AUC $ in eideriv
Argenti et ais2
Pdza$rip~n
AUC/F s r-iiar to youn~
lHu son et als~
I ansoprazo!e
AUC, 1668
n~,'n!L per hour
Rebo~etine
AUC,}}106
!/S#'mL per hour
AUC, 8 4b
n$/rnL pe~ hoiJr 4~
Fluoxetine
ti/~,4 dat,s
ti/2, 5 da>~s
No!fluoxet he: tia,
i 5 days
Norf uoxetine: ti£,
,;0 days
Nicotine
Ci, $ " i % ~
Ci%Jiopran/
CI uncha!lgeci ti£,
~ 30%~
Berama!lN et ai "~
Fb!vc,~, nd Preseurn 85
Differ~ noes not dinicall v
sianificant
Pdoiande~ et ais6
Gutier~aL and Abramo~Jit/sx
No ;38e e%ct
S~ngier et aiss
AUC, ~ 25%~
No dose chan~e !equired
Pqassar~lla et als9
%lrqsal sJ:
Oseltsn!ivir
Flderb !Tean 8J years
Renai Ci $
Ziprasidone
tus for n/en,
}J hours
ti/; *OP V40!Tlei/,
4 i hours
ti,; for fen,
S/hours ~
[J/S ~oP worn@i/,
53 hours ~
C! urJect~d r,,/age
Wilner eL ai9°
A!iopu~ inol
Ci, i b /
!!L/rnin per<$
Oxipurinoi CI 037
niL/rain per r~
CI unJrecced
Oxipu~inoJ CI
0~4 n]Jnqin
per K~4~
Active rr esJboiiTe
C! reduced in elderly
7 i ~3 years)
[iJN/heim et ai 9i
No age e~*ect a*te~
single dose ;Jr!d popuiaiion
PK studies
/~ varik and Koeiie ~
Dose aUjustrnent not needed
n elde! iv
Le Liboux el ai9s
Cyclospo~ ine
P,ilu,,oie
CI un fleeted ti£ ,
P,epagiinide
Cinetics ur!a¢rerled
Sioutrarnine
K netics uns~Mcted
A(£ivo desmethvJ n!etabolit~s
rl-!e~-Ul ed
bqind et 8194
RFapentine
Ci/~, $ }%%~
bdo dose chan£e
r eGOrr~rrlencec
//sun• et ai95
Diphenhyd! an!u!e
UnJrecsed
Age 3'i 76 years
P ycho~qotor e'~c cs
unchanged
bcc#one et 8£196
ti/s, 37 hours
h/creased sedatk/e U'ccB
Piatten et ai9z
Alpl 8~oiar~
bqo change in Ci/b
Seda£k~e and FEG effe<ts
not incraased
4spian et al9s
CiloS~aLOl
Kinetics una**ecsed
Aces e50 years
Suri et al vv
Mida, oiam
ti/l, 3 3 hours
"qatorp et alss
(contir ued)
282
B ~ Cu mck
The Americ~z Jca~'~¢~[oS Geriatric l~h~rm~co~/~er~Zy
Table II. (Continued)
DF,J~
t I.~eN}
~OlJl- ~
,~o
]ment
\@*t~l ~ll ....
ZoimilrilDtan
CI/F 1667 rr!bmin
~I,F 156i
mL/mhq
,n~.>,cnar:~e ilq parent or
desl'rlLl"
"*~-'il7! metsbolite
,sor!ceN+!~atic r!s
PF,ck et M I00
TisFstir:e
A U C /;" n<imL
p@l h o d
AUC, i03 nS,'mL
Pacier? vdth epileps 7
JNC:UCtiCIq occurled 1!-!
i eiderl 7 group
Snei eL al I°i
pel
J~ o f J r
Honteiui<ast
No charge h! Ci
Cardesarts!
A U C i ~ o'/ -~50%
Zhao et ai 3i
rqo 8CCUl//dlatioN ~Ath
biubne! et ai i°~
, ~ FO!qlC CJOSilt£
~@lt,n@ol~
,-
o i
~rl
v~ V ,
ti£: i 8 6 hours
No change in ci/b
~ ) o s e UD t o ,i ~' !.N~5/.~,Cj,
',,,Vor,£ eL 8! !°s
~_ii }% r n L / f i n *
t 1 2 , 7 i 0 hours
Dose !~eciuctiolq
r @co rq~qesG@C]
Richens et ai i°~
Ci/b $
i~rbinsfine
Nedein]sn et ;Jii°b
Vinoreibiqe
Ci unchan£ec
HistoI iosi 7oun8 8roup
orio
Se! t!aiire
AUC: 24 hours
in 7oun$ males $
~]0 PNDa!ed ,@ith TUFNSIes
or old rna.les a£ 700 rns/d
% n M i d eL aii°/
Dolasetror
N o chsrise
% d u c e d scti,,e r,~el;~boiite
not alterec i!l elde~ iy vs
Dernpse 7 et sl i°s
l lbl.~r!~ dJ )'~LJl I~
q ',}/ b ]rld,~
A~,C to ~4 hours
u!sdqsn~ed
et ~i i°6
group
inc!@8 @c: Fe DOll e OT
]sber et aii°9
C pepdde iF: eioeri},
31/~ll (JITI@I~@FIC@II! sJ~@
D@~'~/(S@!q 8[oups
Buproplon
Elderly at risk or accurnulatior~
. ,~
•me~boiites
weet
et ai i io
Nef&zodol/e
~LJC t
~.!netics are ~online r
5~rbhai7~ et ai iii
~il@utoN
C!/F decreased
N o di~T'rence ir d i s
Braeckrnan et sl lls
Fiudox'sciiiin
Ci reduced *
i -
~.~ C#cj ;J!qC} F@F81
Gath et ai2s
J@8~F~dilC(I Jn elderi, ,s
historicsi youn£ 8 o u p
Nethyil-~rednisc ic ne
C i 359 m l / h
per ~'.y
tij,~0
3 hours
Ci, Z 3 / rnLlh
Cl, i9 J h
ti/2,47 hours
CI, 7 _/l-~
ti,,z: 58 hotiFs
Ic ms£ore et ai i is
Arltib? per*ensive e'*ec~
reis?ed to plasrca levels
AL, e r n e t k / i b
ti£, 19 5 4 hours*
Einu~tic ~
Su~en~nii
Amiodipir!~
Potel!tiaJ TOt increased
io!!~ terns toxicib,
Hcirners et ;~i 114
Torsi and *'ee
~l!etics ~
pkoy~ics-¢
Rud7 @t ;jj116
Col, hicine
Ci 10Si/h
Cl, S 5 / h *
PotentbJ ~o! ir!creased LoxJcit;,
~,ochdi et alB
~ardobprii
A U C : 87 iq~IrnL
per J~oul
AUC, 97 !q~/!]]L
per hour
% H i a r A U C % r tra-~dolr@riia¢
n both a~e F4roups
AnLPypertcnsive e ~ c t ~
~ r n e r et al Ii7
t lacdonsid ~t
"= ;a,•
,i •i~
(.~l it!hunG)
283
T}~eAmerican ~¢~r,~r~cal o~Geria~ ic Pbarma~o~;~era~y
B~ Cu ~a~k
Table Ik (Continued)
Dlu~
4,ur ~{
Eideri)~
Co nrr~ent
£,etur@[ice
No need "or close -squstment
in eJqerly
Pan et 8J I19
CJ, 08 rnJmin
per k8~
Dose re< uction r,y "b%
Or,emauer et ai2~
Cdtriaxone
(i, J~ L/h
tim 69 h o u r
NO chan~e fi-orn hiscorlcal
>'our~ 8-aup
Oeny et alia°
Etodobc
l'qo chan~e in AUC
No e*rect of :s~e on kinetics
of enantio~ers
Broc(- et all21
Prs,,*#~sb£Jn
AUC ? in elderly
w o r n e ~ o!]I~,
Indome~ha4n
CI, 14 rnL/rnin
per kr£
Clarithrc, r%,cu!
CI, 4/6 mi/!Tin
C!, 300 mi/rail! ~
H}~dmQ, metabolite alo
eieva?cd Dose adjustr,-ent
not needed
Chu et al Isj
Bambuterol (prodlu$
ofterbuGJline)
CI, 232 Lib
per KI
Ci: J 22 i i h
per ~
lerbusqine A U q was i 5 fold
8reaier in eJde!Jy
i~r
Amlodipine
tb/,48 hours
"JaiPli% prolonged compared
wit ~ historical youn~ ~roup
Dose ~eduction suegested
EiiiotL et al is4
%d~5~sdine
No chanee in Ci
~;~£ of absorution also sirdia~
Elier et ai i2s
Flurbipro*~r~
Ne chanee ir cc,%l Cl
"~ae dru~ Cl co! related with
abe in pa~ierts wiLh RA
Kean et aJr,6
Ci, 0}~9 Lib
per k8
CI, 03~i i/h
per k£~
Old a~e ',6 J d4 },ears)
Prirc hard et al's
Duloxetine
Ci/F dec!eased ~Jith a~e
Fen!ales only
ABe only explained 3% of
the varia~ice
Skh!ner et ai is/
P~ochlorpera/iee
tl//, 7 5 13OiJiS
/-inetics similar ca hi Loncai
;/oun8 8r)up
lash et sl its
Onda!lsetioh
Ci, 035 _,'h
per ~<
et ai i2s
Old u$e {/S 84 years)
Ticlopidine
Nean age,
29 yea! s
Pqean 8~e,
/0 7ears
A U C , } Lo3foid
greaier tha~ i!l JO(JFI~d~
k bJ£life ~4 da~s fo~ ~,oun~
Sled 38 da,~'s*o!" elderly
foiiowin£ r~uitiple dosin 8
Shah et al is9
Quirine
ti£, i0b houls
ti2, i84 hours~
Ci 1~
Cautior! wiLh use in
?s/arlwh ?loJ! u k e t 8 i j 30
CIiF unchanged
F~e ~acton increased in old
Elderly ased ohio, 66 years
Dru~ e%cf a~e dependent
cJ3wir!~herqrrler
lossi Ci,
i24 mL/mii!
per k:~
F~se fl-action clearsr!ce
decreased and dru 8 e%ct
increased in elderly
o nne @t ai i 32
AUC doubied in ekierly
Dese udjus b~,~ent
BaK-i et ai ~ss
Glyburide
Ox~epam
Nisoldipine
Fetal Ci
i44 mL/rni!!
per r.~
uJder p e r s o R
@t 8J 13i
re,'o rr iqqerldeq
SuM!ianii
lnitiaivj $ C!
n d ti£ ~
E#~sc~on !espiracio~/ incrsased
n elderly
~la~eo
e t a Ji 3¢
contir ued)
284
B ~ Cu ~ &
Tb~ Amer¢c~n Jor,~rr~Nof Ger¢~r~c P b ~ r ~ , s o ~ e r ~
Table II. (Continued)
bung
~'it~
Edr(>pl-onium
I abetaioi
Elder i,>
ti/?, 57 min
Cl= i 2 1 mL/min
per kg
tl/:,, 84 min*
c , 59 r~L/mJn
per k~~
CI, , 3 3 mL/rnin
~er h8
'~,, ii 7 !s-L,,'rnJn
per kg s
L:i,48 L/h per %
Benasep!-il
Ke!:o POis C
1.12' ~ 7 h 0 u r
C o ~ , ~ er,t
Pfi~-cimal action and
titration o. meMrnai action
sip-liar in r,oth 8~oups
No dir%rcr,ce in w!~euJ or
flare suppression
N~tteo et ai ~
q:-'~ -~3 eL 8i G6
~1 i k
No kinetic in%faction
,',,it,= N:~AJDs
Nichoison et ;3l i37
,~~, ~o-' L/b , o r kg
Eidedv aged 6(t 68 7ears
-~occi et aJi38
Benazep i;~L
A U C ~-30% b~ rest~
....
Ben;seprii <netics una#~acmd
by age
J aJser et ails'~
*"i Q' b i j-,ojr.~
Dose iedlicdo!/ susge4ed in
eider patients
jaJJad e- aJ i4°
Ci $ in eideri7 ~
Ketanserin
Rerur erice
Peak and
t!OiJ~h
Gould e~ aJ27
CONCeNtI~StiONS UNchaNged
De'F~#opl,_@oxyphen~
Nexiietine
CJ/k
Aged 21 28 >,ears
,Li> 12 3 hours
.~l, J0~ I-NL/TiN
per ~8
I!T]I!L~I results for
ti2, 14~ hou!'s
,~,ooC'~ !~NL/,O-;-.h
©er K8
N O Need f o r dose adiJdst!T@n=t
oral pl~rn~ clearance (cleaa/ce of drug aqer oral a,JrlinisTrador,);
dec~l~a,/ce; $ s<adsdcall7si;sniqcant decrease ELC
toid al-lP,rkis:Vd voJume of disll-ibudon; NSAJE s
%tad ticall7 significant difference
POLYMORPNISM
norc:ex':ro propo%,phene
AND AGING
There have been Few investigations on the possibility
that the polymorphic expression of genes for drug
metabolism changes with aging, Tiffs raises the inter
esting gerontologic question o[ whethe~ certain poly
morphisms may have adverse or advantageous effects
on snrviv~l, an idea that requires fi~ther exploration,
Some studies have demonstrated fl~at polymorphism
extends into old age and may have siguificant conse
7
qnences, Pollock et ali,47 in\estigated
the frequency of
expression of slow merabolizers o£ debrisoqnin in 175
D
',J- ecr b@J
~@ e}t# a 42
based on kineLics
SR
su,~ained release; ~
tatl ticsJJ7 sJgni~ca!rt incroaqe; CI
electroencephaiographic: Css ~eddy s{ste concerltra£ion; <~
non cel-oid~JJ al% hsfia¥1i~a!Ol'7 dl-ugs
[ 14C]erythromycin breath test, in 24 healthy volunteers
aged 70 to 88 years and compared with data from
younger adults, No age difference was noted,
Approaches of this nature, when feasible, can be per
formed on larger numbers of individuals to better
define relationst~ps between aging and &rig metabo
lism in suitable populations,
GENETIC
Fianagan eL aii4i
q~ea 70 79 ye;ss
ProJonsed ti, 2 and
ir creased A U C ~
syqerrqc ©born&
Ulschan£ed s%* sticaJJ7: P,A
r eurr ~
unmedicated, healthy subjects aged >59 ye~u's (mean
age, 75 years), There was no relationship between age
and the frequency of CYP2D6 polymorphic pheno
types as shown by the metabolic ratio of debrisoquin/
4 hy&oxydebrisoquin m'ine concentrations, The pro
portion of slow metabolizets in tiffs g;onp approached
the lower range deternfined in a younger population,
Thus, polymorphic genetic expression of CYP2D6
remains conserved into old age, raising the concern
that elderly, slow metabolizers remain at risk of adverse
effFcts from important subsr~ates fbr this e n ~ m e ,
including norttiptyline, metoprolol, thioridazine,
paroxetine, venla£axine, perpheuazine, and others, The
same authors noted that in a group o[ 45 elderly
patients treated ~ith perphenazine, 5 patients who
were identified as poor CYt) 2D6 merabolizers had sig
nificantly greater side ef{Ects than the 40 extensive
metabolizets, ~48 Thus, as this example indicates, there
may not be a di£f~rence in the frequency of expression
285
27~eAmerican J(~*rna~ ofl GeriarHc Pgarmaco~l~era#y
B ~ Cu ;ack
o f slow metabolizers in ti~e older population, but such
indi\iduals may be at uniquely high risk for dose
related adverse reactions.
The interaction between age and g e n o ~ p e in deter
mining dose reqnirements is 6arthez exemplified in a
study of warfarin dosage required to reach therapeutic
anticoagulation (international normalized ratio, 2.0
3.0) in a group of 121 patients aged 24 to 90 years. ±47
These individuals also were genowped fbr C¥P2C9,
the enzyme responsible fbr tt~e metabolism o f the
genantiomer, which is 3 times more potent than the
R enantiomer. Polymorphism o f the 2C9 gene occm's,
and 2 alleles CYP2C9"2 and C Y P 2 C 9 " 3 have
~10% or 5%, respectively, of the activity o f file wild
wpe. Age was a determinant of dose reqniremenns, but
geuotype added further to the dose prediction.
Therefore, fbr those aged 85 years, heterozF'gotes for
CYP2C9"3 required ordy 2 m g o f warfarin daily corn
pared with 3.1 m g daily in those w~thout the
CYP2C9"3 allele. Thus, the phenotypic effect ofpoly
morphism was retained into old age, wifl~ a 33%
decrease in war fa~in dose reqnirements in heterozygote
poor membolizers.
DRUG C O N J U G A T I O N A N D A G I N G
The discussion to date has pertained to microsomal
phase 1, CYP mediated drug metabolism. Many drugs
also are metabolized by synthetic phase 2 conjugation
reactions such as ace@ation, g[ucuronidation, and sul
ration, with glucuronidation being the most ubiquitous
conjugation pathway. In a prior review; it was con
d u d e d that conjugation reactions were afDcted little by
age. 4 There is no romancing evidence since then m
change that conclusion. Glucu~onidation and sulfation
were studied in ~it~o in human liver samples from 22
subjects aged 40 to 89 years using acetanlinophen as
subsuate. ~ ° There was no significant effect of age on
either pati1~ay. The rates o f clearance by hepatic ~ u
curonidation o f benzodiazepines such as lorazepam, ?~l
oxazepam, ~2 and temazepam "~3 were insufficiently
altered to suggest that age is a determinant o f glu
curonidation capacity. Comparison o f rates of acetyla
lion between age groups is complicated by polymor
phic distribution, and studies m date do not agree on
whether there is any change in acetyhmr phenoWpe
distribution in relation to age. ?~4 n~,6
LIVEN SIZE A N D A G I N G
As discussed, the reasons fior d~e age related decline
in hepatic drug metabolism (Table I I ) are not well
established. Some experts, including Schmucker and
284
Woodhouse, have invoked the age related reduction in
liver size and by inference, in d r a g metabolizing capac
it?; as a possible mechanism. ~°,~7,6~ ~s7 Wynne et al, '~8
using g~ay scale niuasound, observed a significant neg
alive correlation between liver volume and age ( P <
0.001), whether expressed in absolute terms or per unit
body weight. The reduction in volume was on the order
of" 20% to 30%, similar to reductions in clearance
of some drugs, such as ti~e prototype phenazone
(antipyine). However, an age related decline in liver
mass does not predict an obligatory reduction in elimi
nation o f metabolized drugs in the elderly. For example,
Swift et al±~9 conducted a study that included groups of
healthy individuals aged 20 to 29 yea~s and 75 to 86
years, and hospitalized patients aged 70 m 89 yea~s.
They noted that, compared with the young group, liver
volume was decreased in both older g~oups, but the rate
of elimination o f antipyine was decreased only in the
older healthy group. A h h o u g h the elderly hospitalized
patients had reduced liver size, the rate of antipyfine
clearance was simila~ to that in healthy young persons,
suggesting that enzyme activity per unit volume of liver
tissue was increased in ti~e older hospitalized patients.
Thus, there is not always a decline in drug metabolism
w-ith reduction in liver mass in tile eldefl G and the vari
ability of in vivo drug metabolism euz3/me activity may
also play a role in some populations.
LIVER B L O O D FLOW, DRUG ELIHINATION,
AND AGING
Hepatic drug metabolism can be categorized according
to the extraction ratio o f dr ugs as they pass through tt~e
liver. Drugs with a high extinction ratio (>0.7) as they
pass through the liver after IV adnfinistration have
flow limited metabolism, whereby the rate o f hepatic
blood flow deternfines the rate o f metabolism and sys
mmic clearance. Using indocyanine gzeen as a marker,
a significant negative correlation was observed between
age and apparent liver blood flow ( P < 0.001), whether
expressed in absolum terms or per unit body weight. I~8
Similarly, a significant negative correlation was
observed between apparent livez blood flow per unit
volume o f fiver (liver perfusion) and age ( P < 0.005).
Thus, one would expect, under the right conditions, a
decline in the systemic clearance o f drugs with a high
exr±'action ratio witfi age. In accordance with this pre
diction, the systemic clearance oflidocalne, n6° propran
olol, ~6~ labetalol, ±6~- and verapanfil ±°; was reduced in
older subjects after Br adminisuation. However, other
studies did not show a decline with age. 4 The clinical
relevance o f this observation is limited by the fact ttxat
flow funited drug metabolism is restricted to situations
in which such drags are given intravenonsl}~
FRAILTY, ILLNESS, A N D DRUG M E T A B O L I S N
The discussion to this point assumes that when m & i n g
comparisons of pharmacokinetics between different
a d ~ t age g~oups, die individuals included typically are
diulcally stable and healthy. This provides tellable
gerontolo~c data regarding age effFcts. However, in
realit}; most elderly recipients of medications are not
necessatily well and many are "frail," meaulng they are
not fully mobile arid ate dependent on others for activ
ities o f daily living. =64 In addition, many receive medi
cations when unstable at ill. Thus, in practice, the geri
atrics paradigm supersedes the gerontological. The
question, then, is whether flailty or illness alters drug
metabolism in older persons. Williams et al±6~ using
esterase (a phase 1 enzyme) as a probe, noted that
plasma aspirin estetase activity was similar in healthy and
flail young adults as well as healthy elderly adults, but
was decreased in a sample of flail elderly subjects. Tiffs
appeared to be due m a decrease in the quantity of
enzyme rather than in the Kin, a measure o f activity of
the enryme. 166 The clearance ofacetaminophen was sig
nificantly lower in the fit elderly than in the fit young
subjects, and was lowest (P < 0.01) in the flail eldedy
subjects s67 Clearance expressed pet unit volume oflivez
was similat in the fit young and fit ddefly subjects but
was significantly reduced in the flail subjects. TFds was
likely due m reduced partial metabolic clearance to the
g[ucuroulde merabolite pet' unit volume o f liver that was
markedly reduced in the frail elderly ( P < 0.01) cam
pated ~ t h the fit subjects. Further investigation by that
group established tllat the clearance o f metocloptatnide
was sin'dlar in the young arid fit elderly but reduced in
the flail dderly subjects compared w-itb the young
( P < 0.05), both when expressed in absolute terms arid
per unit liver volume (liver volume, meast~ed by ultra
sound, was unaffected by age o r flaiJty). 29 There were
no differences in proportions cleated as the free drug or
as the sulfate at giucntoulde merabolite widfin or
between groups. This suggested that the decrement in
flail individuals was riot due m a decline in liver volume
but to impairment o f conjugation pathways.
Illness and stress can alter drug metabolism. Plasma
aspirin esterase activity was significantly ( P < 0.05)
reduced in elderly patients after hip fracture or elective
hip replacement and recovered toward normal at recu
peration after tile acute event. ?68 Older patients with
community acquired pneumonia had lower esterase
(benzoylcholinesterase, butytylcholinesterase, acetyl
cholinesterase) but not aspirin esterase activity c a m
pared ~Mth a healthy control group. ~69 These activities
ate riot age dependent in healthy individuals] ~9 In
contrast, a lesser stress such as an open hernia tepak did
riot alter these same esterase actixSties in young or old
patientsY ° Such data for these arid other agents ±7± ate
o f importance in suggesting that drug metabolism may
be further altered in flail or sick older patients, adding
m the heterogeneity of drug metabolism arid, as a
result, of dose t equkements in old age.
AGE-RELATED M O D U L A T I O N OF
DRUG METABOLISM
An important gerontologic concern is the possible loss o f
adjustment of function in response to exogenous infin
ences; lack of t espons~veness would point to a decline in
adaptability o f function. Tiffs can be ascertained by cam
paring the e['Dct o f inhibition and, more impotrantl 5
induction o f drug metabolism by other compounds in
young and older persons. In recent atffmal studies, tlte
expression (messenger tCNA, protein, a n d / o r catalytic
activity) of a number of constitutive and inducible iso
forms of CYP were compared in 5 and 23 montll old
male and female Sprag~e Dawley rats. '~72 The indue
tion eftEcts of low concentrations of phenobarbital
were measured. With rite exception of male specific
C Y P 2 C l l , the investigators observed fitfle senescence
assodated reduction in preinduction or induction levels
of CYP2B1, 2B2, 3A1, 3A2, 2C6, 2C7, 2C12, and
2C13 in eitller male or female rats. H a m a n in ~4tro stud
ies o f a microsomal monooxygenase enzyme, atyl hy&o
catbon hydroxTlase , were conducted in isolated periph
eral blood monocytes from young and elderly donors;
the rate of induction was independent of age. q73 Despite
these in ~4tro investigations demonstraflng no effect of
a ~ n g on induction o f activity, tllere is disagreement con
cerning the persistence of the e['tEct of enzyme induction
in viva into old age. Dichloralphenazone, at a dosage of
20 m g / k g nightly for 2 weeks, increased the rate of elinti
nation o f quinine and antipF~ine (phenazone) in young
subjects but not in old subjects. ~74 Like~ise, T w u m
Barima et als7~ reported an induction effect of rifampin
on clearance ofphenazone in young volunteers that did
not occur in older subjects. In contrast, otlter studies
have demonsuated preservation of tile et'Dct of induc
tfun o f drug metabolism in old age. Glutethhnide, a
potent enzTme inducer, increased the clearance o f
antipyrine (phenazone) by almost 70% (mean [SEM],
flora 22.8 [4.5] m L / m i n m 38.3 [7.6] m L / m i n ; P <
0.001) in a group of patients aged >70 years. ±7~ Since
phenazone, as previously discussed, is a snbstrate fbr sev
287
27JeA~ericaez ~o~*r~zMofGeriarJic Pbarfeeacoff~erapj
B5 Cufack
eral cytoc[~'ome isoenzymes, this suggests that tile ettSct
of giutethhnide w~s unlikely to have been selective for
one pathway, given the magnitude of the induction.
Czowley e t 31i77 performed a study of the ef'f~ct o f the
enzyme inducer phen}<oin in young and old cigarette
smokers and nonsmokers in which the phenymin dosage
was carefully selected so that plasma concentrations were
sinfilar in both age groups. As in odmr studies x78 180
(although not all 7s,79) related m the ef'ti~ct of aging on
the induction effect o f tobacco on drug metabolism, cig
arette smoking also was associated with an increase in
"d~eophylline cleasance in older persons (Figure 4).
Baseline plasma theophylline clearance was 309/0 lowe~ in
old compared w-~t)1young nonsmokers (mean [SEll , 34.0
[2.5] vs 48.8 [2.6] m L / h per kg; P < 0.001), whereas
the small age difference between old and young smokers
(86.0 [8.4] vs 72.4 [8.011 m L / h per kg) v#~s not sigdifi
cant, Smoking was associated with an enhanced rate o f
"dleophylline dimination in both age g*oups. I'~7 They
found t)tat ptet~eam~ent w4th phewtoin proportionately
increased the clearance of theophylline to an equal
degree in both age groups and in smokers (mean [SE]:
young, 42.6% [6.5%]; old, 47.3% [3.6%]) and nonsmok
ets (mean [SE]: young, 56,3% [8.8%]; old, 45.4%
[6.4%]). The effect o f phenymin was additive to the
induction effect of cigarette smoking in both age gtoups.
Induction o f drug metabolism may also alter drug
bioavallability in older persons. Rifampin rseatment for
9 days decreased the mean (SD) bioavallability of
propafenone fi'om 30% (24%) to 4% (3%) (P < 0.05) in
a group o f older extensive CYP2D6 metabolizers. 18±
After oral propaf'enone was admiNstered, clearances
through N dealkylation (mean [SD], 6 [3] vs 26 [16]
m L / m i n ; P < 0.05) and glucuronidation (178 [75] vs
739 [533] m L / m i n ; P < 0.05), but not S hydroxylation,
were increased by rifampin, suggesting substantial in
duction of both phase 1 and phase 2 metabolism.
(Interestingi% 5 hydroxTlation , the CYP2D6 mediated
reaction, was not induced, consistent ,Mth the theory
that tiffs isoenzyme is not inducible.) Thus, enzyme
induction can occu* in the elderly, indicating an adap
tive response, with possible eff~c~s on bioavallability in
some cases, and can affect both phase 1 and phase 2
hepatic drug metabolism.
Inhibition of drug metabolism does not typically
im~olve an adaptive response on the pa~t o f the host but
rather a drug enzyme interaction. Age related changes
in drug inhibition would therefore imply changes in
enzyme structure or Nnction. However, there is no
convincing evideuce that this occu*s. Mtial studies
using cimetidine, a well known inhibitor o f drug metab
olism given to young and older individuals, reduced the
'8°i
160 i
Q_
j
120i
8
IO0 J
/
/
/
/
140
e
(D
<
O.OOS
r
]
Control
Phenytoin
//
j
4oi
2O i
i.ooo,
P< 0.001
//iie
5/"
]
,o i
60
t£
/
....
......
"
qP< 0.001 i
E
Control
Phenytoin
Control
Phenytoin
Phenytoin
Control
0
Young
Old
Nonsmokers
Old
Young
1
Smokers
Figure 4. Effect of age and phenytoin on the total plasma clearance of theophyNine in nonsmokers and smokers, Singledose studies of theophylline pharmacokinetics were conducted before and after 14 days of phenytoin administration. Brackets represent mean (SEM). Reprinted with permission] 77
288
B 5 Cu ;c~ck
clemance of phenazone (69% vs 79% of young and old
contxols) and desmefllyldiazepam (51% vs 65% o f young
and old conuols) m a simila~ extent in both age
groups, i82 Subsequently, others confirmed that inhibi
"don ofphenazone metabolism by cimetidine occurred
to a simila* degree (~-.25%) in both young (21 26 years)
and older (65 78 y e a s ) healflly volunteers, zss Similat'ly,
inhibition o f theophylline elimination was rioted to be
similas in young and older adults, ±7~,;s4,] s ~ although the
older groups were only 56 to 68 yea~s o f age in one
study isa arid 60 to 74 yeats in another study. ±8~ Because
the effect of cimetidine is dose related ±s~ and because its
elimination decreases with age, the preservation ofint~
bition in old age might be due to t'dghet plasma le~'ds
o f cimetidine. However, Vestal et all7s repotted that
altho ugh cimetidine concentrations were elevated in die
older gtoup, d]ere was no telationsbdp between cimeti
dine concentrations and the change in theophylline
clearance at the dose o f cimetidine used (1200 r a g / d ) .
Fluoxetine, a known inhibitor of CYP2C19, when given
to y o u n g and elderly healthy persons, inhibited
m e p h e w t o i n metabolism similarly in bodl age groups,
Th~ Americ~ez Joe*r#¢MqFGeriatric Ph~rm~coffJer~
increasing the (S) to (R) mephen}toin ratio 3 to 4
fold (P < 0.01), consistent with irtldbition of merabo
lism of the CYP219 substrate Gmephenytoin. s-~
Inhibition can also be adddtive when 2 intfibitots are
added to a regimen. Loi et al ]sd detected an additive
intfibitot y effect of cimeddJne and ciptofloxacin on the
plasma clearance o f timophylline in both young and old
healthy male arid female volunteers. Individuall E cimet
idine and ciptofloxacin produced proportionate de
clines in plasma theophylline cleazance that weie shnilaz
a m o n g the 4 groups (range, 23.4% 32.7% decrease).
The combined regimen yielded further impairment
(range, 35.9%42.6% decrease) in theophylline elimi
nation compared ~s~th each agent alone (laigure 5).
The proportionate reduction in fiormation clearance o f
theophylline metabolites was simila~ a m o n g rtle 4
groups. Thus, age did riot affect the individual ot addi
five effect o f 2 inhibitots of metabolism.
RENAL
DRUG
ELiMINATiON
Many &'ugs are eliminated via the kidney, ~u~d tile
amount excreted depends on the sun] o f the effects o f
m Cimetidine
L~ Ciprofloxacin
[]
Cimetidine
+ ciproflo~cin
8
[9
g
F._c
I
-50 1
L
i
40
JL
*
*
i
L~
I
i
]'i[
NS
*
]
i
i
i
J~
NS
*
J
L
1
i
JL
*
J
*
I
1
YM
YF
EM
EF
Figure 5. Proportionate changes in total plasma theophylline clearance after treatment with cimetidine, ciprofloxacin, and
cimetidine + ciprofloxacin. Asterisks and brackets denote statistically significant different groups. Single-dose studies of theophylline pharmacokinetics were performed after 7 days on each treatment. YM = young male;YF =
young female; EM = elderly male; EF = elderly female.~-P < 0.05. Reprinted with permissionJ 86
289
27JeAmerican Joe*rnM of Geriatric Pharmaco~berapy
B~< Cu;a&
glomer uiar fiks'ation, active tubulas secretion, and passive
reabsorption. The degree to which these uept~on fianc
dons are affbcted by aging ~411 deternfiue any age rdated
change in renal drug diminatiom The ef'fbct of'aging on
renal function and thereby on renal & u g diirfination has
been comprehensively reviewed by Muhlberg and
Platt. ~6 A ~ n g is associated with definite tffstopathologlc
changes, including a decrease of renal weight, a ttffckeu
ing of the intt arenal vascttlas' intima, sclerotic changes o f
the giomeruli, and infiluation of" chto~c inflammatory
calls and fbrosis in the st~oma, q6 Functional changes can
occut ~fffll a~jug as a result o f pathologic changes, it*°7
More recent studies have suggested tlmt file reduction in
renal glomerular ultsafiluation is due in part to sts'uctttral
changes that lower die single nept~on glomerular c o e f
ficlent and in past to file reduction in file actual number
of fianctiorffng glomeruff, q88
The classic studies by Kowe et al:t89 asid Faulstick et alsg0
demonst*ating an age related decline in glomerulas
filtration rate and in tubular function using cross
sectional data were supplemented by further work by
this g*oup. They demonstrated tlmt in normal individ
uals in the Baltimore Longitudinal Study of Aging,
cross sectional analysis by 10 yeas age groups showed
a progressive linear decline in creatinine cleasance (used
as a measure of'the glomemlas filtration rate) fi'om 140
to 97 m L / m i n / 1 . T 3 n g between file ages of g0 and 80
yeats, while longitudinal data showed asl acceleration o f
the rate o f decline in creati~fiue deas'ance w-kh advanc
ing age. ~± The decline in various tubular ~nctions (eg,
tubulas maximums, concenuatiug and diluting abil
ities, acidification) tend to pas'allel die deaseases in
glomeruias filtration rate. *St Subsequent longitudinal
studies in 446 healthy persons fiom the Baltimore
Longitudinal Stud>' of Aging showed dlat die decline in
creatinine clearance was not inevitable arid that orie
"dlird o f individuals showed no decline, while in 7 indi
viduals, creatiulne clearance actually inaseased ovei
time. 192
As could be pt edicted fiom the discussion above, the
rate of elimination o f drugs excreted mainly by file kid
ney (Table I I l 2°,9±,193~12) generally is reduced in the
elderly. Thus, dose requkemencs of & u g s excreted
maiuly by the kidney, in accordance ,a4th the age
related change in renal ihuction, should be reduced in
many, but not all, older persons. Antibiotics fbrm an
important group o f & u g s cleased mainly by the kidney
and ate reviewed by Meyers and wilkinson} ±3 In addi
lion, limited data suggest that reduced clearance o f
active metabolites of certain & u g s may enhance thera
peutic eff]ect at increase the risk of toxicity, pasticulas'ly
290
in very elderly patients w-itl~ more likely renal impair
ment. Exasnples include N acetyl procaiuamide, file
active metabolite of" ptocainasnide2±4; morphine 6
glucutonide, die active metabolite o f morphiue2~; and
normepetidine (norpethidine), the metabolite o f
meperidine (pettlidine) }~6a 17
Estimation of cteatinine cleasance v~4f help deter
n~ne d~e dose. Measurement o£ serum creatinine con
centt'ation alone in elderly patients can be very mis
leading; it is well known flint because o£ the deaseased
production ofcreatiulne due to reduced muscle mass in
such individuals, a normal serum cteatiulue may prevail
in file presence o f renal impairment. Cteatiulne clear
ance often is estimated from the serum creatinine level,
using uomogtasns or fbrmulas that provide a reason
a b l ~ a l t l l o u g h not highly accutate estimate of" cleas
ance}~8 222 One caveat is tlmt the accuracy o f these
methods is best in healOlier individuals and may be
even less dependable in ill patients and in those at the
extremes o f renal fianction. One of" file most widely
used methods m calculate aseatinine dearaslce is file
Cockctoft GatJt fbrmula, 22~ which includes age, body
weight, sex, and serum as eatinine as variables in the ca[
cuiation according to file following ~armula:
Creatinine deasance ( m L / n t i n )
[140 age]
>: body weight ( k g ) / s e r u m creatinine ( m g / d L )
>, 72
For women, tim result o f file above fbrmula is multi
plied by 0.85.
Calc uiatiou o£ aseatiulne deasance using this fbt mula
is somewhat helpgul in disasimiuating between normal
and impaired renal function and rims usual at reduced
& u g doses. 224 ~-towevet, it has been f'ound by some
investigators to underestimate glomerubs flirtation late
in healthy older individuals in w h o m pharmacokinetics
o£ tenally excreted drugs (eg, ateuolol, hy&ochloro
tbiazide) was unchanged} 2~ Thus, while estimation of
creatinine clearance assists in predicting dose require
merits of tenally excreted drugs in the elderl>; fl~e
metl~odolo~ 7 is not tfighly accurate. One should sup
plement dose prediction x~th plasma monitoring when
using & u g s w[fll a low therapeutic ratio such as
digoxin, lifllium, and the aminoglycosides. In other
cases, it is prudent to measure aseatinine cleasance fbr
guidance of" die dosage o f toxic diugs that are not
assayed, such as cisplatin or methotrexate, especially in
ddefly patients ~ t h impaired renal function.
Little teseasch has been devoted to file eff]ect of"
aging on renal tubulaz drug t*ansport. Reideuberg et
Table Ill. Effect of aging on pharmacokinetics of drugs excreted mainly by the kidney.
Drug
'<our@
Elder i}.
P,~rerer ce
Comrr~er t
Arniloride
IR/snal Ci,
300 r,~L/rqirl
R/anal Cl,
102 mL/rnin~
Deceased tubuisr
secretion
Somogyi et al i93
O%,purinoi (active
me::~bolite of
siiopurh!oi)
Ci, 0 3 /
mL,'rri r~
per %
Ci, 074
p%'rdn
per i%~
(/i 'x3 y~sr s)
Erect on xarthine oxidase $
-~rnheirn et aJ9i
Methot~axat~
P 1 4b ,years
65 83 yeai~s
CI of :o,~N and flee irwersel}~
!elated t',~ age (P < 0001)
Bressoik~ et 8J1~4
Bumetsside
btal and renal CI $
NaZriuretic e'~cc: $
Oberbauer et al/°
Cefpodoxirne
Renal clearance $
Half life t
P obably not irnporTant
No dose ;Jdju trner t reeded
Borin et a1195
]%embi%, ef ;Jlj~c
Vuncorrtcin
Ci $
Daily dose 18l rag/i<x
h! eioerl7
Gu%, et ;Jii~'
Aztreor arn
AUC, 194
ua/rnL
per hour
AUC, 469
~8,'rril
per hoiJF
l ower coses rna/ be
appropriate in elderly
Pleye! s eL aligts
Meropenern
CI 203
!nl/rain pe
i / 3 r-s
Ci, 139
mLlrnin pal
i/3!r~ ~
Use lo',,ve! dose
t u c 7 in men cnl7
Liungberg uNd i'qiJsson Ehie i'~
Cet;Ndime
ci $
Jr! acut>J7 ill pKients cornp red
w t h young histo! icai controls
jONSSOr! and %/:sider z°°
Ofioxacin
P 8srna und
rerai CI i
C! 23
rnL/r-@!~
Reduce dose
Bsrsr! et ;si'°i
CI, 83
mi/mi!!
N%,(u s eL siz°s
C! cf both
Ampiciiiin/sLilbac~n!
Axithrorrycin
r !oiinso et ~i;°z
AUC. l i
~g/n!L
p c ! hoiJF
~,(, l/
~g,'rnl
per hOUFx<
No dose chsnae needed
Coates et aJs°a
No~oxacin
ci
$
No dose change needed
i e p g e et ;~@0s
Ciplofioxscin
CI $ ,,~
No dose chsn~4e !seeded
f renal %notion preserved
Hire:a et sl '°6
hi4odcS /oung
Cot itrols
Cadfioxacin
AUC increased
,,,/20% 0 %
No need +,,;rdose adju4!Yent
i aCresJ et aiso/
I evofioxacin
~ odest dP#l ence,
No need b r dose adju4ment
Chien eL aF @'
Cebs~xime
Ci dec!es-ed
'~,'iti~age >60 /cars
Imipenern
Decreased compared
with NoIq/!sis
Clearance declined with
renal fiJnct on
Pietrosu~ et 8isi0
~ o n et a@ii
M ~ ? I hOUFS~<
Moder~.Ta dose reductior
FobrtiJl~!! et 8Jsl/
Pipersciiiin
HKE
i2 houls
%tsdsqcslJysiaificart di%rence
CI sys~emlc pia" @ clearance; $
tdtisdcally significsJit decrease; $
U!Jen et :si'°9
Kstisdc JJ7signi~csrt increase blRT
r ~esr~residencetime
291
27JeA~ericaez ~o~*r~zMofGeriarJic PbarfeeacoffJerapy
B5 Cufack
al2?4 demonstrated several years ago that the renal
cleatance of procalnamide (which is depeudeut on
glomerular filtration and tubulat secretion) was
reduced in older subjects. The mean (SD) ratio o f pro
calnamide cleatance m creatimne cleatance was 2.9
(1.6), consistent w-~th renal tubular secretion. In addi
tion, although the data ate heavily influenced by young
individuals aged <30 years, it appeared that the ratio o f
procainamide cleatance to creatinine cleatauce declined
with age as a continuous vatiable, suggesting an age
related reduction in tubular basic drug secretion. In
subjects aged >30 yeats, however, it did not appeat that
aging influenced net tubular secretion. In other studies,
the net renal tubulat secretion (ratio of drug dearat~ce
to creatinine clearance) o f organic bases including
cimefldine ;;6 and amilorid# 9s was uot affected by age,
although elderly subjects had impaired creatimne cleat
ance. Interpretation o f the cimetidine data is obfns
cared somewhat by the fact that cimetidine levels were
increased in the elderly, at~d cimetidine is known m
inhibit renal excretion of creatinine, spuriously altering
creatinine clearance. More recenfly, Ujhelyi et al22~
demonstrated that the renal excretion of pindolol, a
racemic drug that undergoes both g[omerular filtration
and mbulat secretion by the organic base t~at~sporter,
was not affected by age in healthy young (mean [SE]
age, 26 [4] yeats) and older (mean [SE] age, 71 [5]
yeats) individuals, despite a significant reduction in cre
atinine cleatance in the older group. This suggested
that renal tubular secretion was preserved in the older
group. Taken together, these studies suggest that in
adults, in contrast to glometular Éiltration (creatiulne
clearance), there may not be much change ~a~th age in
renal tubular tsanspott of organic bases.
Does aging af't~ct the response of organic base t~ans
potter to stimulation or inhibition? This question also
was addressed by Ujhelyi et a l y 7 The clearance of each
pindolol isomer was estimated and the response was
assessed to both a m m o n i u m chloride (increases the
urine proton gradient), w[fich increases renal cleat'ance
by increasing tubular secretion o f pindolol, and m
t~imethopfim (inhibits the organic base transporter),
which reduces renal pindolol cleatance by decreasing
tubulat seatetion. As can be seen in F i g u r e 6, while
baseline pindolol renal cleatance did not differ between
age groups, a m m o n i u m cNoride inateased pindolol
renal clearance to a greater extent in the young, and
trimethoptim competitively decreased pindolol renal
cleatance similatly in both age groups. There was no
stereoselective effect o f age. Thus, aging can blunt the
ability of" the organic base renal tubular transporter m
be stimulated, an example o f the decline in adaptability
~ t h aging. Further work needs to be done on the pos
sine eff:ect o f aging on the activity of other renal ttans
porter mechanisms such as P g p .
Age dependent changes in renal mbulat function can
alter drug effect in the kidney. A prime example is the
effect o f orgat'dc acid diuretics in the kidney, such as
6arosemide and bumetanide, wt~ch ate substrates for
the organic acid t~ansporter in the proximal tubule. An
[
800 ]
i
6oo i
~g
i
[]
Control phase
~
NH4CI treatment
Trimethoprim treatment
P = 0.008
P= 0.016
4oo i
T 1
i
2oo
R-(+) Yng
R-(+) EId
S-(-) Yng
S-(-) EId
Figure 6. Pindolol renal clearance during control phase, ammonium chloride treatment, and trimethoprim for each isomer (R-[+] and S-[-]) and age group.Statistical comparisons (analysis of covariance) demonstrate tl~at there was
a significantly greater increase in renal clearance of either isomer in young compared with old subjects after
ammonium chloride treatment. Yng = young; EId = elderly. Reprinted with permission. 227
292
B ~ Cu ;nck
earlier study indicated that fmosemide kinetics were
altered so that after IV bolus admir~stmtion of 80 m g ,
the mean (SE) amount ofunchanged ffirosen'dde in the
urine dining the first 30 minutes after administration
was 30 (6) m g in the young but only 20 (4) m g (P <
0.01) in the elderly male volunteers, as a result o f
reduced renal tubular secretion. 2~ In concordance,
further studies indicated that imtial sodimn excretion
was reduced in older persons: during the 30 minutes
after furosemide administration the increments in
excretion o f mine, sodium, potassium, and furosemide
were significantly smaller ( P < 0.05) in the elderly. ~29
LikewisG bmnetanide renal clearance was reduced in
older healthy outpatients compared ~ith young volun
teers, consistent with reduced renal mbula~ secretion in
the older' group. 2° With t)xe decline in tlxe urinary
excretion rate o f bumetaulde, the urine flow gate and
sodium excretion rate were reduced in the older (aged
65 73 years) compazed with the younger (23 35 years)
volunteers (Figure 7). The fractional excretion o f
sodium was unchanged, signifying that the reduction in
response in older subjects was due to a reduced n u m
be~ of functional nephrons.
These data elegantly indicate that the overall activity
o f the renal tubulaz oggardc acid r~ansporter declines
~ t h age and, as a result, tl~e effects o f dimetics
transported by tills system to their site o f action a~e
reduced in older persons.
In summary, renal clearance of & u g s by filtration is
decreased in older persons commensmate with the
0 Youngsubjects
• EldeHysubjects
C
A
15~
o
ad~
~.-=
~o mE
e
The Americ~ez J¢~n~'~¢~[of Geriz~ric Ph~xm~coff~er~py
E
.-= ~
I
6]
i
10 d
r
4i
5 "|
1
i
=i
0 I ~
-
0
[
/
I
2
3
r
I
4
5
]
r
I
0
3
2
Time (h)
I
i
4
5
Time (h)
D
4 I
il
o
od
3 i
o
1.5
\\
[
o~
I
I
~j
I
,,x, _~
.-= 1.0 J
=i
_E o
I
D
O~
•
1
0
i
I
r
2
Time (h)
r~
3
T
4
,
5
I
..........,
2
3
4
5
Time (h)
Figure 7. Time-dependence of (A) urine flow rate, (B) urinary sodium excretion race, (C) fractional excretion of sodium
(FENa), and (D) urinary bumetanide excretion rate after IV bumetanide (0.5 mg) in 6 younger" (28 [I] years, mean
[gEM]) and 8 elderly (68 [ I ] years, mean [SEM]) subjects.The cumulative urine volume, urine sodium excretion,
and urine bumetanide excretion were all significantly decreased in the elderly group. Reprinted with permission, t°
293
27~eAmericg~ ]o~rnM ofl GeriarHc Pbarmacod~erapy
B ~ Cu ;ack
decline in creafinine clearance. C~eatinine clearance
declines in man}; but riot all, older persons and can be
estimated from the serum creatinine using published
formulas or nomogtams. When using drugs ~ith a low
"dtetapeutic ratio, estimation o f the cteafinine clearance
helps deternfine the initial drug dose but, when possi
bl G should be complemented by therapeutic d r a g
monitoring. Renal tubular organic base transport does
not appear to be altered, whereas organic acid tr'ansport
appears to decline with age.
CONCLUSIONS
Pharmacokinefics is complex and dependent on many
different factcns, including body composition arid func
dons or muldple organs and enzyme systems, Thus, it
is not smpfising that the effect o f ' a ~ n g on phatmaco
kinetics is not simple and depends on the net effect o f
aging on these individual determinants o f d r a g han
dling. Some processes, such as drug absorption, do not
show age dependence, whereas others such as renal
drug filtration generally decline with age. The effect o f
age on other pharmacokinetic parameters such as drug
elimination by metabolism is variable, and an adequate
explanation fbr such variation has not been established
as yet. More recent work is helping to illustrate the
effect of aging on transporter mechanisms in different
tissues, including the small bowel and the kidney. The
effect o f aging on pharmacokinetics in humans cannot
be seen alone in gerontologic terms but must also be
viewed in the clinical context. Then it is appa*ent that
the effect of organ disease (eg, renal or hepatic dys
fhnction) or clinical status (stress or fiailty) may greatly
outweigh any effect of aging. Finally, on a cautionary
note, most gerontologic studies o f phamuacokinetics
fail m include the very old (age >85 years), and our
knowledge o f pharmacokinetics in this age group is
very limited.
ACKNOWLEDGMENTS
This material is the result of wore s ~ p o r ~ d ~
resources and use o f facilities at the Boise VA Medical
Center, Mountain States Tumor and Medical Resea*ch
Institute, Boise, Idaho, arid the University o f
Washington, Seattle, Washington.
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A d d r e s s c o r r e s p o n d e n c e to: Barry J. Cusack, M D , Ctfief, Geriatrics Section, VA Medical C e n t e r ( 1 5 1 ) , 5 0 0 West
F o r t Street, Boise, I D 8 3 7 0 2 . E mall: barty.cnsack@med.va.gov
302