Læknablaðið : fylgirit - 01.05.1978, Side 63

Lars Wibell
From the Medical Clinic, University Hospital,
Uppsala, Sweden.
Abstract:
Naproxen was given at routine dosage to
patients with advanced renal insufficiency. After
5 days of treatment the serum level of the drug
was lower than usually reported for patients
with normal glomerular filtration rate. One
explanation for this seemed to be a shorter
biological half-time of the drug in uremia. It
is suggested that a decreased binding to plasma
albumin in uremia facilitates conversion of
naproxen into 6-desmethyl naproxen. The latter
metabolite was found to accumulate in plasma
from the investigated patients.
Introduction:
From published data (1, 2, 3, 4, 5) on the
metabolism of naproxen it may be suggested
that, because of a pronounced 99 per cent bind-
ing to plasma albumine, this drug has a long
biological half-time of about 14 hours. The
only important metabolite in man seems to be
6-desmethyl naproxen, des-methylation occurring
in the liver. This metabolite can usually not
be demonstrated in significant amounts in plasma.
After the administration of labelied naproxen the
total recovery of radioactivity in urine is high,
about 95 per cent. Both naproxen and the
metabolite may then be demonstrated in the urine
and the excretion of conjugates, such as
glucuronide, is 4 - 6 times higher than the
excretion of free metabolite and naproxen.
This paper is a pilot study of the metabolism
of naproxen in patients with severiy impaired
renal function. Such a study appeared to be
worth while as anti-rheumatic drugs are often
given to patients with a reduced glomerular
filtration rate; and as the excretion of naproxen
and its biological products mainly occurs via the
kidney.
Patients and methods:
Six patients on maintenance haemodialysis
volunteered for the study. They were 39 - 57
years old and suffered from terminal renal
failure. The glomerular filtration rate (GFR)
ranged 0 - 3 ml per min and the dialysis treat-
ment comprised 6 hours twice a week.
THE METABOLISM OF NAPROXEN
IN RENAL INSUFFICIENCY
Three patients were given 250 mg of naproxen
as a single dose, on a day between two dialysis
treatments, and blood samples were drawn at
intervals up to 8 hours after dose.
Four patients received naproxen 250 mg twice
daily for about one week. During the period of
investigation dialysis treatment was performed
twice. The drug was given at 9.00 a.m. and
9. 00 p. m. , corresponding to the starting time
of dialysis. Blood samples were drawn before
and after dialysis treatment and the plasma
values before dialysis were thus obtained 12
hours after dose and the post dialysis values
were obtained 6 hours after dose.
Estimation of the plasma levels of naproxen and
6-desmethyl naproxen was performed by a reversed
liquid chromatography method (6) and in one of
the single dose experiments by gas chromatography
(Syntex Pharmaceuticals, Maidenhead).
Results :
Single dose experiments. Regarding
the metabolite, 6-desmethyl naproxen, measurable
plasma values were not found in patient H.N.
(gas chromatography). In patient E.G. an
unidentified substance disturbing the analysis of
6-desmethyI naproxen was present. Plasma
values for the metabolite was thus only obtained
in patient R.O. and are shown together with the
plasma values of naproxen in Fig. 1. The plasma
concentration of the metabolite seemed to increase
continuously during 8 hours. In Fig. 2 the plasma
naproxen values are shown for all three patients.
The biological half-time for the drug, calculated
from 4 hour and 8 hour values, was less than 8
hours in these three patients.
Continuous treatment with 250 mg
x 2 . The mean values of naproxen and 6-des-
methyl naproxen found before and after dialysis
in patients V.H. , K.G.A. and H.N. are shown
in Table I. Significant amounts of the metabolite
were detected and there was a tendency to some-
what lower values after dialysis. As regards
naproxen itself the plasma values were somewhat
higher after dialysis (6 hours after dose) than
before dialysis. After some days of continuous
treatment the obtained plasma values of naproxen
61