Br. J. clin. Pharmac.

(1983), 16, 104-105

PHARMACOKINETICS OF VALPROIC ACID IN YOUNG AND

ELDERLY SUBJECTS
S.M. BRYSON, N. VERMA, P.J.W. SCOFT & P.C. RUBIN
Clinical Pharmacokinetics Laboratory, Department of Materia Medica, Stobhill General Hospital,
Glasgow G21 3UW

The disposition of valproic acid was studied following single dose intravenous administration in seven
young male volunteers aged 20-35 years and six elderly male in-patients aged 75-87 years. Following
administration of 400 mg sodium valproate, blood samples were collected for 48 h and valproic acid
concentrations analysed by enzymatic immunoassay. The median elimination half-life was 7.2 h in
the young subjects but 14.9 h in the elderly patients (P < 0.01). However, clearance did not differ
significantly between groups, the values for young and old being 0.69 and 0.58 1/h respectively. The
prolonged half-life resulted from a greater volume of distribution in the elderly. The median values
(I/kg) for young and old were 0.13 and 0.19 respectively (P < 0.01). These pharmacokinetic changes
are unlikely to be of clinical importance.
Keywords valproic acid pharmacokinetics young subjects elderly subjects

Introduction
Old age is known to be accompanied by several
physiological changes which could alter drug disposi-
tion (Greenblatt et al., 1982). However, recent
evidence suggests that it is difficult to generalise about
the effects these changes might have on pharmaco-
kinetic indices. Although liver metabolism decreases
in the elderly, not all drugs which are metabolised
show a decreased clearance with age (Rubin et al.,
1981). Similarly, the physiological reduction in renal
function does not uniformly lead to a reduced elimi-
nation rate of drugs cleared by this route (Rubin'et
al., 1982). It is therefore wise to study each drug
individually in order to assess the influence of age on
its disposition. Sodium valproate is an anti-convulsant
which is widely used in all age groups and we describe
here a study on its pharmacokinetic profile following
intravenous administration to young subjects and
elderly patients.
Methods
The study protocol was approved by the Research
and Ethical Committee of the Greater Glasgow Health
Board (Northern District) and all participants gave
informed written consent. Seven healthy young
volunteers aged 20-35 years and weighing 50-75 kg
were compared with six elderly patients aged 75-87
years and weighing 40-80 kg. The elderly patients
were recruited from long-stay geriatric wards and
none was receiving any medication likely to interact
with sodium valproate.
104
Sodium valproate (Epilim, Labaz) was administered
intravenously in a dose of 400 mg over 5 min. Blood
samples were collected from an indwelling heparinised
venous cannula (Venflon® ) at 5, 10, 15, 20, 30, 45,
60, 90, 120, 150 min and 3, 4, 5, 6, 8, 24, 32 and 48 h
after administration. Valproic acid concentrations
in serum were analysed by enzymatic immunoassay
(Syva, Palo Alto, California). Concentration vs time
data were fitted to a bi-exponential equation of the
form
Cp(,) = Ae -at + Be -t
using a non-linear least squares regression programme
with reciprocal weighting. The area under the con-
centration vs time curve during a blood sampling
period was calculated using the trapezoidal rule. The
extrapolated area beyond the last data point was cal-
culated by dividing the concentration at the time of
the last sample by the terminal slope obtained from
the computer fit of the data. Clearance of valproic
acid was calculated by the model independent rela-
tionship
Dose of sodium valproate x 0.87
CL
AUC(x
The coefficients of the bi-exponential equation were
used to calculate the volume of distribution at steady
state (Vss) according to standard techniques assuming
a two compartment open model with elimination from
the central compartment. Data were compared by
Wilcoxon Rank sum test.
 SHORT REPORT 105

Table 1 Pharmacokinetic indices of valproic acid in young subjects and elderly

patients: median (range)
t'/2zIZvss CL
(h) (l/kg) (Ilh)
Young 7.2 (5.9-12.6) 0.13 (0.11-0.16) 0.69 (0.59-0.96)
Old 14.9 (11.2-16.9)* 0.19 (0.15-0.27)* 0.58 (0.46-0.66)
*P < 0.01 compared with young.

Results was a weakly significant inverse relationship between

serum albumin concentration and V,, (r = 0.65, P <
The major pharmacokinetic indices are shown in Table 0.05).
1 and concentration vs time data for a representative
subject from each group are shown in Figure 1. Both
the distribution and elimination half-lives were signi- Discussion
ficantly prolonged in the elderly. However, the greater
elimination half-life resulted not from any significant The clearance of certain drugs such as chlor-
difference in clearance but rather from a greater diazepoxide, chlormethiazole and propranolol has
volume of distribution in the elderly patients. There been shown to decrease in the elderly. Other drugs
100
such as diazepam, lignocaine and prazosin have no
80 change in clearance but prolonged half-lives resulting
70 from a greater volume of distribution in older age
__60 6
50 groups. Valproic acid falls into this latter category.
40.[
30 % The drug ordinirily has a small volume of distribu-
n 2020 C
tion, is highly protein bound and glucuronidation and
oxidation are the two major routes of metabolism
ci o (Gugler & von Unruh, 1980). It is likely that the
increased ratio of fat to lean tissue which is seen in the
C) 0vs elderly will have contributed to the increased volume
Co~~~~~~~~l
of distribution seen here. In addition, the fall in serum
albumin which occurs with age will also have made a
CD) contribution as suggested by the weak but significant
inverse relationship between serum albumin and V,
These changes in pharmacokinetics observed in the
4 8 12 16 20 24 28 32 36 40 44 48 elderly patients are unlikely to have any clinical signi-
Time (h) ficance and no modification of dose seems necessary.
Figure 1 Concentration vs time curve following intra- The work described here was performed by NV in partial
venous administration of 400 mg sodium valiproate in a fulfilment of the requirements for the M.Sc. degree in
representative young (0) and elderly (0) subject. Clinical Pharmacy of Strathclyde University.

References
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(Received January 14, 1983,
accepted March 3, 1983)