Br. J. clin. Pharmac.

(1983), 16, 65-70

PHARMACOKINETICS OF KETOPROFEN IN
THE ELDERLY
C. ADVENIER', ANNIE ROUX2, C. GOBERT:, P. MASSIAS4,
ODILE VAROQUAUX' & B. FLOUVAT2
'Laboratoire de Pharmacologie, Facultd de Mddecine Paris-Ouest et Institut Biomedical des Cordeliers,
15, rue de l'Ecole de Medecine, F - 75270 Paris Cedex 06, 2Laboratoire de Toxicologie, H6pital Ambroise Parc.
Avenue du Gendral de Gaulle, F - 92100 Boulogne, 3Hospice Intercommunal, 74, avenue de Stalingrad,
F - 94120 Fontenay-sous-Bois and 4Service de Rhumatologie, H6pital Antoine Bdcl&re, 157,
rue de la Porte-de-Trivaux, F - 92140 Clamart, France

1 Pharmacokinetic constants of ketoprofen (Orodis , Profenid ) were determined in 10 young

adults (24.9 + 1.3 years) and seven elderly patients (86.3 + 2.4).
2 Following oral administration of a 150 mg dose of ketoprofen, no difference in tmax was observed
between the two groups. However, compared with younger subjects elderly patients showed a
significant increase in t1y2,. (2.72 + 0.22 vs 1.77 + 0.16 h; P<0.01) and AUC (70.4 + 6.4 vs 29.13 +
2.02 mg 1-' h; P < 0.001), a non-significant reduction of Vd/F per kg bodyweight (0.145 0.016 vs
0.213 + 0.0281 kg-') and a decrease in total clearance CLT,F (0.037 0.002 vs 0.071 0.004 1 h-' kg-',
P < 0.05).
3 These results suggest that the glucuroconjugation of ketoprofen is slowed down by age.
Keywords ketoprofen pharmacokinetics elderly subjects

Introduction
The hepatic degradation of many drugs is known to
be diminished in the elderly. This has been demon-
strated for type I reactions, such as oxidation of
phenazone or phenylbutazone (O'Malley et al.,
1971), chlormethiazone (Triggs, 1979), quinine
(Stevenson et al., 1979), acetanilide (Playfer et al.,
1978) and clobazam (Greenblatt et al., 1981). On the
other hand, demethylation of diazepam (Klotz et al.,
1975) or lignocaine (Triggs, 1979), reduction of
nitrazepam (Castleden & George, 1979) or hepatic
oxidation of nortryptiline (Braithwaite et al., 1979)
warfarin (Hewick et al., 1975) and theophylline
(Nielsen-Kudsk et al., 1978), do not seem to be modi-
fied by age.
Ketoprofen (Orodis , Profenid- ), a non-steroidal
anit-inflammatory drug that is mainly glucuroconju-
gated (Populaire et al., 1973), is widely used in France
for the treatment of rheumatic disorders in old-age
patients and since its metabolism in elderly patients
does not seem to have been investigated, it was
deemed necessary to do so. The present work is a
comparative study of the pharmacokinetic constants
of ketoprofen in elderly subjects and young healthy
volunteers.
65
Methods
Subjects
Ten young male volunteers (mean age 24 + 1.3 years)
and seven elderly people (six women and one man;
mean age 86 + 2.4 years) in an institution entered the
study after being fully informed of its purpose and
giving written consent. The elderly people were
suffering from a variety of minor ailments, e.g.
moderate arterial hypertension, cerebral and peri-
pheral vascular disorders and digestive disorders, as
well as from 'rheumatism' for which they occasionally
received ketoprofen. Before the experimental pro-
cedure began, both volunteers and elderly people
underwent thorough clinical examination. All were
found to have haemoglobin, plasma BUN, electro-
lytes, bilirubin, total proteins, prothrombin, creatin-
ine, SGOT and SGPT levels within the normal range
for their age and sex. Patients with definite cardiac,
renal, hepatic or gastro-intestinal disease, or with a
history of cerebral vascular accident, or on major or
multiple chemotherapy were excluded beforehand.
None of the subjects had taken drugs for 48 h at the
time of investigation.
66 C. ADVENIER ETAL.
Experimental procedure
All subjects fasted for 12 h before receiving an oral
dose of ketoprofen (Profenid ) 150 mg in three 50
mg capsules. They continued to fast for 2 h, then were
allowed a light meal.
Venous blood samples were drawn through a Teflon
catheter 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 9 h
after dosing. Blood was collected into heparinized
tubes; plasma was separated by centrifugation and
stored at -20C. Urines were collected by fractions
during 48 h in the young subjects and 24 h in the
elderly patients.
Ketoprofen assay
Ketoprofen concentrations were measured in plasma
as free drug and in urine after NaOH hydrolysis using
a high pressure liquid chromatography method
(Bannier et al., 1978; Farinotti & Mahusier, 1979).
For this purpose, 0.5 ml of plasma, to which 5 jig (0.1
ml) of benzoyl-3-phenylbutyric acid had been added
as internal standard, were extracted by 10 ml of ether
in the presence of HCI (N 0.5 ml). After centrifugation
and dehydration with anhydrous Na2SO4, ether was
evaporated to dryness at 40C under nitrogen. The
residue was dissolved in 200 ,ul of elution solvent and
100 Al were injected into the chromatograph.
Separation was performed on a 30 cm x 4 mm i.d.
column filled with 10 ,um ODS, using as a mobile
phase a mixture of 0.025 M phosphate buffer at pH 3,
methanol and acetonitrile (45.15.25) at a flow rate of
2 ml/min. Ketoprofen was detected at 250 nm by
means of a spectrophotometer (Schoeffe SF970).
The accuracy and the precision (expressed as rela-
tive standard deviation %) of the method was deter-
mined by inter-day assay of several samples spiked
with ketoprofen: when 5 mg/l were added to plasma,
the amount found was 5.12 0.26 mg/l, n = 54, CV:
5.02%, when 10 mg/l were added to urine, the
amount found was 10.03 0.23 mg/l, n = 10, CV =
2.34%.
Calculation
For each subject, the rate constant of the terminal
phase of elimination, X7, was calculated by non linear
regression of plasma levels vs time, from the second
hour; corresponding half-life was
t, = 0.693/Xz (1)
Areas under the curves were measured by the
trapezoidal method and extrapolated to infinity
according to
Ct
AUC. = AUCt + - (2)
xz
where Ct is plasma concentration of the last sample.-
Total clearance CLT;F (F being the bioavailability
factor) was obtained from
_ D ..
CLT/F = (3)
where D is the dose administered (in this case,
150 mg). The volume of distribution V area/F was
calculated as:
V area/F = D (4)
AUC. x Az
With urinary data, half-life of glucuroconjugates,
t,, was calculated using the rate of urinary ex-
cretion, AU/At, in function of time.
Statistical analysis of the results
Statistical analysis of the results was performed using
Student's t-test.
Results
Mean plasma levels and cumulative mean urinary
levels of ketoprofen against time in young and elderly
subjects are depicted in Figure 1 and Figure 2 respec-
tively. Tables 1 and 2 give the pharmacokinetic values
as calculated from plasma data of each subject, Table
3 from urinary data.
Time to peak plasma level (tmax) of ketoprofen was
1 h on average after dosing, without any statistical
difference between aged and young subjects (0.90 +
0.20 vs 1.30 + 0.20 h respectively). However, plasma
levels of the drug were consistently higher in elderly
patients than in young volunteers. Peak level (Cmax)
was 20.9 + 1.5 mg/l in the former group vs 13.1 + 1.5
mg/l in the latter group (P < 0.01). Similar differ-
ences were observed between the two groups with
AUC (P < 0.001) and ty (P < 0.01). In contrast, the
volume of distribution V area/F and the total clear-
ance CLT/F of the drug were lower in elderly patients,
irrespective of whether they were expressed in abso-
lute values or in relation to body weight.
Urinary excretion values necessarily included both
free and glucuroconjugated ketoprofen. The urinary
curves indicated that the excretion of ketoprofen was
delayed in elderly patients as compared to young
adults. This was confirmed by the smaller proportion
of drug recovered from early urine fractions in the
elderly group (46.6 + 2.9% vs 66.0 1.7%).
Discussion
The metabolism of ketoprofen has been the subject of
numerous studies in animals and man. The elimina-
tion of the drug in man was found to be of first order
 KETOPROFEN PHARMACOKINETICS IN THE ELDERLY 67

E
C
X 2
0.
0
4)
-W 1

Time (h)
Figure I Ketoprofen plasma concentrations against time in young adults ()and elderly patients (O) after oral
administration of 1.50 mg.

process, i.e. independent at dose, at least up to 500

Time (h)
Figure 2 Urinary excretion of ketoprofen in young
adults (0) and elderly patients (0) expressed as cumu-
lative percentage of the 150 mg dose administered
orally.
mg orally (Cailld et al., 1978). Ketoprofen is largely
glucuroconjugated on its acid radical, and a negligible
amount of unchanged drug is excreted in the urine
(Populaire et al., 1973; Upton et al., 1980, 1981; Kaye
etal., 1981).
In the present study, the results in young adults are
in agreement with data from the literature concerning
elimination half-life, total clearance (Ishizaki et al.,
1980; Upton et al., 1980) in percentage of drug re-
covered in the urine and rate of excretion (Ishizaki et
al., 1980; Kaye et al., 1981). In elderly subjects tmax
was very close to that observed in young adults, but
Cmax values were significantly increased while the
volume of distribution decreased.
The distinct, though not significant, decrease
observed in the volume of distribution Vda/F
(expressed per kg bodyweight) in elderly subjects
may be compared with that reported by Simon et al.
(1972) with propicillin K, by Ewy et al. (1969) with
digoxin and by Divoll et al. (1982) with paracetamol
(acetaminophen). Like these compounds, ketopro-
fen is a polar substance which seems to be distributed
preferentially in the liquid compartmnents of the body.
68 C. ADVENIER ETA L.

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 KETOPROFEN PHARMACOKINETICS IN THE ELDERLY 69

Table 3 Urinary elimination and half-life, tl2 U, of glucuroconjugates of

ketoprofen after oral administration of 150 mg ketoprofen to 10 healthy
subjects and seven elderly patients.
Subjects U24 U48 t,,2U
(mg) (%) (mg) (%) (h)
Young adults
1 95.2 63.5 95.5 63.7 2.4
2 102.7 68.5 102.7 68.5 2.4
3 90.2 60.1 90.4 60.3 2.3
4 99.4 66.3 99.6 66.4 1.9
5 86.1 57.4 86.2 57.5 2.5
6 94.2 62.4 94.5 63.0 3.1
7 113.1 75.4 113.2 75.5 1.9
8 107.5 71.7 108.0 72.0 1.9
9 98.7 65.7 99.0 66.0 2.5
10 103.2 68.8 103.3 68.9 2.4
Mean 99.0 66.0 99.2 66.2 2.3
s.e. mean 2.5 1.7 2.6 1.7 0.1
Elderly subjects
1 75.1 50.1 2.5
2 67.2 44.9 3.6
3
4 80.9 53.9 - - 2.8
5
6 73.5 49.0 1.8
7 52.9 35.3 3.2
Mean 69.9 46.6 2.8
s.e. mean 4.4 2.9 - - 0.3
p < 0.01 < 0.01 NS

In the elderly, the liquid compartments seem to be
reduced to the benefit of fat compartments (Mitchard,
1979; Crooks et al., 1976), and this would explain
why, fat-soluble compounds, such as diazepam or clo-
bazam have an increased volume of distribution in
elderly patients (Klotz et al., 1975; Allen et al., 1980;
Greenblatt et al., 1981). Another possibility is that
the decrease in Vda F observed in our elderly subjects
was due to a difference in sex, as noted by Divoll et al.
(1982) with paracetamol; all our young subjects
were male, whereas six out of seven elderly subjects
were female. A change in F values in our older sub-
jects is unlikely (Greenblatt et al., 1982), F is close to
1 in man (Delbarre et al., 1976).
Other changes present in elderly patients in this
study were an increase in elimination half-life and
AUC and a decrease in total clearance, which
suggest a slower metabolic breakdown of the drug
This is borne out by the decrease in the total amount
of glucuroconjugate excreted in the 24 h urine (owing
to the very old age of the patients, we were unable to
collect the 24-48 h urine), despite the fact that the
urinary elimination half-life(t112U)of these conjugates
was virtually the same as in young subjects. These
data are to be compared with those reported by
Triggs & Nation (1975), Fulton et al. (1979) and
Divoll et al. (1982) concerning paracetamol conjuga-
tion or by Traeger et al. (1973) concerning indo-
methacin metabolism. In elderly subjects, these
authors noted an increase in half-life and a decrease
in total clearance of these two compounds, presum-
ably due to reduced or delayed glucuroconjugation.
In addition, Traeger et al. (1973) found that the total
amount of glucuroconjugates of indomethacin re-
covered in the urine was reduced in elderly people as
compared with control subjects (13% as against
30%). They ascribed this reduction to increased
biliary excretion of indomethacin and/or its con-
jugates in old-age patients. The decrease in the total
amount of urinary ketoprofen conjugates found in
the present study suggests a slowing down of the
glucuroconjugation process but not necessarily a
reduction in the total amount of metabolite formed,
some of which might also be excreted in the bile. This,
however, needs to be confirmed by biliary excretion
studies.
Glucuroconjugation is classified among type II
metabolic reactions which are usually unmodified by
age. It would appear from this study that this is not
the case with every drug.
70 C. ADVENIER ETAL.
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