Læknablaðið : fylgirit - 01.05.1978, Page 71

L. Helleberg, J. Gylding-Sabroe and J. Sylvest
Department of pharmacology, University of
Copenhagen
Departments of rheumatology and physical
medicine in Glostrup and Bispebjerg, Copenhagen
THE EFFECT OF ASPIRIN ON
THE PHYSIOLOGICAL DISPOSITION
OF INDOMETHACIN IN MAN
i
In the treatment of arthritic conditions two or
more drugs are often administered concurrently
assuming that the beneficial effects of the
individual drugs are intensified without a similar
intensification of the side effects. Thus in the
treatment with indomethacin aspirin is p.t. often
prescribed for additional pain relief. However,
it has been claimed that aspirin antagonizes the
antirheumatic effect of indomathacin.*>2
In an attempt to solve this issue several
authors8.4,5,6 have investigated the effect of
aspirin on the serum concentrations of indo-
methacin.
The results have however bcen conflicting -
possibly because various non-specific assay
techniques have been applied for indomethacin
in serum.
As a gas chromatographic method7 has been
developed by which it has become possible to
obtain reliable estimations of small amounts of
indomethacin in biological fluids without inter-
ference from drugs or metabolites of indo-
methacin we have found it appropriate to investi-
gate the effect of chronically administered
aspirin on the physioiogical disposition of indo-
methacin.
TWO-COMPARTMENT OPEN MODEL
RAPID INTRAVENOUS INJECTION

►V, - r ^2

h21-«
fi-oC
t_«t hn-/a
oC-fi
■e-/1*) ( Eq.1)
Material and methods
Eight healthy volimteers of either sex and
between 15 and 37 years old participated in the
study. Indomethacin was injected intravenously
before or after oral treatment with 500 mg or
1000 mg aspirin b.i.d. for one week. Blood
samples for determination of the serum concen-
tration of indomethacin were taken by venipuncture
at various times during 24 hours. Indomethacin
for intravenous injection was kindly prepared by
Dumex, Copenhagen. Each dose consisted of 25
mg indomethacin freshly dissolved in 5 ml
phosphate buffer which was injected over a one-
minute-period.
In order to establish the pharmacokinetic para-
meters the serum concentration vs time curves
for each person were analyzed according to the
two-compartmental qpen model.8
Fig. 1 shows a scheme of the model as well
as some of its implications. The model
describes the kinetic behaviour of a drug on the
k»'TÍf k«' V*-V, -Ja- (Eq.2.JM)
AUC0_t •-£-■ (i. JL .(l-,-/11) (Eq.5)
assumption that it is distributed between two
volumes: a central compartment with a small
apparent volume and a peripherial compartment
of a larger apparent volume. Drugs enter the
system only via the central compartment and are
eliminated exclusively from the central compart-
ment. Reversible transfer occurs between the
central and the peripherial spaces.
Another assumption applies for this model i.e.
that the rate at which a drug is removed from
a compartment is proportional to its concentra-
tion in the compartment, i.e. that first-order
kinetics describe the exit of drug from both .
compartments. It should be stressed that this
model is a purely mathematical tool, it does not
necessarily correspond to specific anatomic or
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