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Studies on the mechanism of ethambutol-induced hyperuricemia.

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Studies on the Mechanism of Ethambutol-Induced
Hyperuricemia
Arnold E. Postlethwaite and William N. Kelley
The effect of ethambutol on uric acid metabolism was assessed in 14
patients, 8 with gout and 6 with tuberculosis. This antituberculous agent
produces hyperuricemia by decreasing the renal clearance of uric acid.
Although the exact mechanism responsible for this effect of ethambutol
remains undefined, several characteristics were observed which distinguish the effect of this drug from that of other agents which produce
hyperuricemia by altering the renal handling of uric acid.
Prolonged administration of ethambutol is
associated with the development of hyperuricemia in about one-half of the patients receiving this antituberculous agent (1). T h e development of hyperuricemia appears to be
related to a reduction in the fractional excre(1). In
tion of uric acid (CuratJCcreatin,nP)
the present study, we have examined the effect
of ethambutol on the renal handling of uric
acid and compared the effect of this agent with
other agents, such as salicylates, diuretics,
ethanol and pyrazinamide, which also produce
hyperuricemia by a renal mechanism.
From the Division of Rheumatic and Genetic Diseases,
Department of Medicine, Duke University Medical Center,
Durham, NC.
Supported in part by US Public Health Service Research
Grant AM14362 and Training Grant AM05620, and
supported in part by a Grant (RR-30) from the General
Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health.
A R N O L D E . P O S T L E T H W A I T E , M D : Senior Assistant
Resident, Department of Medicine, Duke University Medical Center, Durham, NC; WILLIAMN. KELLEY, MD: Chief,
Division of Rheumatic and Genetic Diseases, Department
of Medicine, Associate Professor of Medicine, Assistant
Professor of Biochemistry, Duke University Medical Center, Durham, NC 27710.
Reprint requests should be addressed to: Dr. Kelley.
Submitted for publication Jan 26, 1972; accepted March
22, 1972.
MATERIALS AND METHODS
A series of studies were performed on 8 patients with a
history of gout. These patients were hospitalized on the
Clinical Research Unit of Duke University Medical Center
and maintained on a 70-g protein diet essentially free of
purines for 5 days before and throughout the period of
study. Except as indicated below, these patients were not
taking drugs known to alter the metabolism or renal excretion of uric acid. Each patient received colchicine (1.2 ma)
daily. O n study days, urine flow was maintained at a rate of
1 to 3 ml/min by the oral intake of an appropriate volume
of water. Serum and urine samples were collected over a 2hour period for uric acid and creatinine content before a
single oral dose of ethambutol (1 200 mg) was administered
to each patient. Urine was collected at 2- to 14-hour intervals for up to 24 hours after ethambutol was given. Serum
was obtained at the midpoint of each urine collection
period.
Since both the degree and time of onset of hyperuricemia
induced by ethambutol had great individual variation ( I ) .
several studies were conducted on patients with tuberculosis
in whom significant hyperuricemia had developed while
receiving ethambutol therapy. Six patients hospitalized at
the Veterans Administration Hospital, Durham, NC, were
included in this study. T h e dose of ethambutol administered
to these 6 patients in single doses ranged from 12 to 19 mg/
kg/day. T h e patients were not receiving other medications
known to alter the metabolism or renal excretion of uric
acid; however, they were receiving isoniazid and pyridoxine, and some were receiving streptomycin in addition
to ethambutol. T h e urinary excretion of sodium and potassium was evaluated in 1 of these patients (JK) before and
during ethambutol treatment. T h e effect of ethambutol on
the urinary excretion of these electrolytes was also eval-
Arthritis and Rheumatism, Vol. 15, No. 4 (July-August 1972)
403
m
a
n
P
0
P
Responders
AB Control
Ethambutol
JW Control
Etharnbutol
KB Control
Ethambutol
EC Control
Ethambutol
Nonresponders
HM Control
Etharnbutol
AM Control
Ethambutol
GW Control
Etharnbutol
FT Control
Ethambutol
Patient
12
0
10
0
16
0
0
19
22
0
18
0
22
0
7
0
Time
(hr)
8.0
7.9
7.5
7.0
8.9
9.0
7.3
8.0
8.9
10.0
8.4
9.5
9.4
10.9
6.6
7.9
Serum
urate
(mg/lOOrnl)
+0.7
+0.1
-0.5
-0.1
+1.3
+ 1.5
+1.1
+ 1.1
Maximal
change
10-22
-2-0
8-12
-2-0
-2-0
14-24
-2-0
8-16
-2-0
8-12
-2-0
12-21
-2-0
0-6
-2-0
20-24
Time
(hr)
2.5
2.5
2.4
2.4
1.a
1.5
2.5
3.3
4.7
1.5
4.7
2.9
2.5
1.a
4.0
2.7
( x 100)
Curate/Ccr
+ 32
-17
0
0
-33
-28
-38
-68
Change
(70)
2.0
2.0
1.8
1.6
1.6
1.4
1.a
2.6
4.1
113
3.9
2.6
2.4
1.9
2.6
2.1
UVUratJCcr
(adrnl)
Table 1. Effect of a Single Dose of Ethambutol(l200 mg) on
the Fractional and Normalized Excretion of Uric Acid
+ 44
-13
-1 1
0
-19
-21
-33
-68
Change
(70)
158
158
102
144
164
120
64
62
a4
1 18
116
133
112
121
132
117
Ccr
(ml/m i n)
4
rn
r
r
s
E
0
2
s
0
8
2
7
I
ETHAMBUTOL-INDUCED HYPERURICEMIA
uated in 1 patient with tuberculosis UP) who had not
developed an increase in the serum urate during the administration of this agent. Blood lactate levels were determined
in 3 patients who were hyperuricemic while receiving
ethambutol.
T h e effect of aspirin, iopanoic acid and allopurinol on the
hyperuricemia induced by ethambutol was assessed in several of the patients with tuberculosis. These patients received ethambutol and the other antituberculous drugs,
mentioned above, throughout the period of study. T w o patients were given aspirin (600 mg) at 8 AM on 2 consecutive
days. One week after aspirin had been discontinued, iopanoic acid (3 g) was given to these same 2 patients. At a
later time, 2 patients were treated with allopurinol (300
mg/day) for 1 week. Uric acid and creatinine clearances
were estimated for 10 to 24 hours before and 10 to 48 hours
after the administration of aspirin and iopanoic acid.
T h e influence of ethambutol on the uricosuric properties
of sulfinpyrazone, as well as iopanoic acid, was studied in
several patients with gout. Three of the subjects (AB, JW
and KB), who developed a decrease in both the fractional
(CuratJCcrcatininr) a n d normalized excretion of uric acid
(UVuratJCrreatinine)
12 hours after receiving a single dose
of ethambutol, were given sulfinpyrazone (100 mg) alone
and, on another study day, 12 hours after the administration of ethambutol (1200 mg). Iopanoic acid (3 g) alone
was given to 1 of the gouty subjects, and several months
later this dose was repeated 12 hours after the administration of ethambutol (1200 mg). Iopanoic acid alone was
administered to 2 gouty subjects.
T h e effect of aspirin and pyrazinamide on the uricosuric
effect of iopanoic acid was also studied in an effort to compare these two agents with ethambutol. Aspirin (1200 mg)
was given to each of 3 nongouty hospitalized patients who
had a normal serum creatinine concentration and were receiving iopanoic acid (3 g) for routine cholecystography.
These patients were on a regular hospital diet and were not
taking other drugs known to alter the metabolism or renal
excretion of uric acid. T w o gouty patients hospitalized on
the Clinical Research Unit were given pyrazinamide (3 g)
1 X hours before receiving iopanoic acid (3 9). Serum and
urine were obtained for estimation of uric acid and creatinine clearances before and at various intervals after each
of these agents was given.
T h e effect of aspirin on the hyperuricemic effect of
pyrazinamide was compared to the effect of aspirin on
the hyperuricemic effect of ethambutol. Pyrazinamide
(3 g) was administered alone and, on another occasion,
with aspirin (600 mg) to 2 different gouty subjects hospitalized on the Clinical Research Unit. Uric acid and
creatinine clearances were estimated as described above.
In all studies the interval between the administration of
each drug was determined by the length of time required
for the C u r a t J C c r c a t i n i n e and U V u r a t J C c r c a t i n i n e to
return to control levels. This ranged from 24 hours for
sulfinpyrazone to as long as 5 days for iopanoic acid and
pyrazinamide. All urine was collected at room temperature
using toluene as a preservative.
Uric acid content of serum and urine was determined by
a specific enzymatic method (2). Creatinine content of all
urine was assayed by the method of Taussky (3) and serum
creatinine by a method adapted to the autoanalyzer (4).
Lactate concentration in venous blood was determined by
the lactate dehydrogenase method (5). Urinary sodium
and potassium were determined on a Flame Photometer,
Model 143 (Instrumentation Laboratory, Inc, Boston,
Mass).
RESULTS
W e have previously demonstrated an increase in the serum urate concentration of 2.4
mg/100 ml or greater in 62% of 24 patients
with tuberculosis 5 to 90 days after the initiation of therapy with ethambutol (1). In the
present study we have found that the administration of a single dose of ethambutol (1200 mg)
to each of 8 gouty subjects was followed in 4
patients (AB, JW, KB and EC), within 24
hours, by an elevation of the serum urate concentration ranging from 1.1 to 1.5 mg/ 100 ml
above control values. In these 4 patients there
was a mean decrease in UVuralJCcrcalininr
of 35 % (range 19 to 68 %) a n d a mean decrease
in CuratJCcreatinine
of 42 % (range 28 to
68%) below control values (Table 1). Of the
remaining 4 patients, 2 exhibited no increase
in serum urate or a detectable change in
U V u r a t c / C c r e a t i n i n c o r C u r a t e/ C c r e a i n i n c
after receiving a single dose of ethambutol. One
patient (GW) had a slight decrease in the frartional and normalized excretion of uric acid,
which was not associated with an increase in
the serum urate concentration. One patient
(FT) had a modest increase in his serum urate,
which was associated with a n increase rather
than a decrease in the CuralJCcreatinine
and
t
UVumrJCcreatininc
Ethambutol did not appear to decrease the
filtered load of urate, since the endogenous
creatinine clearance (Ccreatinine)
remained
unchanged, or increased somewhat, in 6 patients and decreased in 2 patients after ethambutol was given (Table 1). In addition, etham-
Arthritis and Rheumatism,Vol. 15, No. 4 (July-August 1972)
405
POSTLETHWAITE AND KELLEY
Table 2. Urinary Excretion of Sodium and
Potassium Before and During Ethambutol Therapy
Patient and drug
_ _ _ _ _ _
JK
Control
Ethambutol
JP
Control
Ethambutol
Time
(days)
UNaV
UKV
(mEq/24 hr)
0
14
92.3
91.7
48.0
40.4
0
2
111.0
112.0
45.5
43.3
butol had no discernable effect on the urinary
excretion of sodium or potassium (Table 2).
T h e uricosuric effect of sulfinpyrazone, an
agent whose action has been attributed to inhibition of the renal tubular reabsorption of uric
acid ( 6 ) , was not appreciably altered by
ethambutol pretreatment (Table 3). T h e administration of ethambutol did not appear to
alter the uricosuric effect of iopanoic acid, an
agent which may enhance the renal tubular
secretion of uric acid (7) (Table 4).This differs
substantially from the results obtained when
patients receiving iopanoic acid were pretreated
with either aspirin or pyrazinamide. Pyrazinamide, an agent which is postulated to produce hyperuricemia by selectively inhibiting the
renal tubular secretion of urate, blocked the
uricosuric action of iopanoic acid, and aspirin
greatly diminished this effect (Table 4).
Ethambutol did not produce hyperlacticacidemia in 3 patients in whom this was
Table 3.
Condition
measured. Blood lactate levels were 7, 11 and
13 mg/100 ml, respectively, in these patients
when they had become hyperuricemic during
the administration of ethambutol. Although no
pretreatment control values were obtained,
these values are well below 20 mg/100 ml,
which is the upper limit of normal by this
method.
T h e administration of aspirin to 2 patients
with tuberculosis who had developed hyperuricemia while receiving ethambutol produced
a further decrease in the CUM,P/CLrrat,n,nc
and an additional increase in the serum urate
concentration (Table 5). As reported by others
(9), aspirin appears to partially reverse the
hyperuricemic effect of pyrazinamide (Table 5).
Allopurinol (300 mg/day) lowered the serum
urate concentration from 12.2 to 7.3 mg/100
ml and 9.7 to 4.9 mg/100 ml, respectively, in 2
patients with tuberculosis who were hyperuricemic due to the administration of ethambutol.
DISCUSSION
Ethambutol appears to increase the serum
urate concentration by altering the renal handling of uric acid. In patients with tuberculosis
who are receiving ethambutol, an elevation in
the serum urate concentration is associated with
a reduced renal clearance of uric acid (1). In the
present study, the administration of a single
dose of ethambutol produced a n increase in the
Uricosuric Effect of Sulfinpyrazone in Patients Receiving Ethambutol
No of patients
Mean change in
Mean change in
serum urate*
CurateGreatininet
(mg/100 ml)
(YOof control)
_ _ _ _ _
~
Sulfinpyrazone
Sulfinpyrazone+
ethambutol
3
-0 5
+95
3
-0 8
+ 102
-~
*Mean change i n serum urate concentration 6 hours after sulfinpyrazone administration compared to
control
+Mean change in Curate/Ccreatlnlne
from 0 to 6 hours after sulfrnpyrazone administration compared to
control
406
Arthritis and Rheumatism, Vol. 15, No. 4 (July-August 1972)
ETHAMBUTOL-INDUCED HYPERURlCEMlA
Table 4.
Condition
___
lopanoic Acid
Alone
Ethambutol
Pyrazinarnide
+Aspirin
Comparison of the Effect of Ethambutol, Pyrarinamide and Aspirin
on the Uricosuric Property of lopanoic Acid
No. of patients
Mean change in
serum urate"
(mg/100 ml)
Mean change in
CurateGreatminet
(70of control)
-1.2
-0.8
f0.5
-0.1
+ 107
+ 132
+
+
-84
+ 23
*Mean change i n serum urate concentration 12 hours after iopanoic acid administration compared to
control
$Mean change in Curate/Ccreatinine
0 to 12 hours after iopanoic acid administration, except for iopanoic
acid plus aspirin when CUrate/Ccreatininewas determined 2 to 12 hours after iopanoic acid was given
Table 5. Effect of Aspirin on Fractional Excretion of Uric Acid in
Patients Receiving Pyrazinamide or Ethambutol
Condition
Ethambutol
Alone
+Aspirin
Pyrazinamide
Alone
+Aspirin
Mean change in
Curatdccreatininet
(70of control)
No. of patients
Mean change in
serum urate"
(mg/100 ml)
2
2
+2.1
+2.9
-36
-53
3
2
+ 0.2
+0.9
-76
-13
"Mean change in serum urate concentration from control after 28 days of ethambutol administration
to 2 patients and 24 hours after aspirin was given to these 2 patients. Values for the pyrazinamide
and pyrazinamide plus aspirin studies represent mean change in serum urate 12 hours after pyrazinamide was given on each study day.
tBased on 24-hour urine samples for ethambutol studies and 12-hour urine samples for pyrazinamide
studies
serum urate concentration of greater than 1
mg/100 ml in 4 of 8 gouty subjects studied. In
each of these 4 subjects, there was also a substantial reduction in the fractional excretion of
uric acid.
In the present study, we have attempted to
characterize the mechanism by which ethambutol produces a decrease in the renal clearance
of uric acid. In normal man, it is postulated that
uric acid is filtered by the glomerulus, approximately 98% of that is reabsorbed in the
proximal convoluted tubule, and approximately
86% of that appearing in the final urine is secreted in the proximal or distal tubule (10).
This hypothesis on the renal handling of uric
acid is based in large part on the premise that
pyrazinamide selectively and totally blocks tubular secretion of uric acid. Recent studies in
the cebus monkey have led to the suggestion
that pyrazinamide may also enhance the tubular reabsorption of uric acid (1 1 ) . If this is also
true in man, then this postulated bidirectional
Arthritis and Rheumatism, Vol. 15, No. 4 (July-August 1972)
407
POSTLETHWAITE AND KELLEY
transport of uric acid within the nephron may
have been significantly overestimated. At the
present time, as in the past, any attempt to
define the mechanism by which a drug interferes with the transport of uric acid within the
kidney in man must be based to a large extent
on the postulated effects of other drugs such as
pyrazinamide. This approach, which is utilized
in the present study, is subject to several significant limitations. First, the effect of a given
drug may not be exactly what it is assumed to
be, as pointed out above. Second, drug-drug
interactions may modify the effect of eithkr drug
in an unpredictable or even unrecognizable
manner. Despite these limitations, this approach still remains the most useful and continues to provide valuable new information.
Based on the current concepts of uric acid
excretion by the human kidney, a n agent could
produce hyperuricemia by a) lowering the
glomerular filtration rate, b) enhancing the tubular reabsorption of uric acid or c) blocking
tubular secretion of this organic acid. It is
thought that diuretics ( 1 2 ) , a n d p o s s i b 1 y
ethanol, lower the glomerular filtration rate by
causing plasma volume contraction and produce
hyperuricemia partially by this mechanism.
Ethambutol did not increase the urinary excretion of sodium or potassium. In addition, the
glomerular filtration rate as estimated by endogenous creatinine clearance did not consistently decrease after t h e administration of
ethambutol. This finding, plus the observation
that the serum urate concentration increases
during ethambutol therapy, actually suggests
that the load of urate filtered at the glomerulus
is increased rather than decreased. Sulfinpyrazone, an agent which is thought to inhibit the
tubular reabsorption of uric acid, was administered to patients pretreated with ethambutol.
One might expect that the uricosuric action of
sulfinpyrazone would be partially blocked if
ethambutol actually enhanced the t u b u l a r
reabsorption of uric acid. However, ethambutol
did not appear to alter the uricosuric effect of
sulfinpyrazone. It is thought that agents such as
408
pyrazinamide (9) and salicylates (13), as well as
drugs which cause hyperlacticacidemia such as
ethanol (14) and furosemide (15), decrease the
renal clearance of uric acid by causing inhibition of its tubular secretion. T h e uricosuric effect of iopanoic acid, a radiocontrast agent
which appears to facilitate the tubular secretion
of uric acid, is blocked by pyrazinamide and
greatly reduced by aspirin. If ethambutol inhibited the tubular secretion of uric acid, perhaps the uricosuric effect of iopanoic acid
would also be blocked by ethambutol. However, ethambutol, unlike pyrazinamide and
aspirin, did not appear to diminish the uricosuria produced by iopanoic acid. Although
these studies did not localize the site of action
of ethambutol, they did suggest that ethambuto1 may affect sites in or on the tubular cells,
which are different from those altered by either
sulfinpyrazone or iopanoic acid.
T h e effect of ethambutol on the renal clearance of uric acid was also compared to that of
other agents known to produce hyperuricemia
by a renal mechanism. Some of the distinctive
characteristics of each of the four classes of
drugs that produce hyperuricemia by decreasing the renal clearance of uric acid are summarized in T a b l e 6. Ethambutol, unlike
ethanol or diuretic agents, did not produce hyperlacticacidemia or an increase in sodium excretion. In addition, ethambutol differed from
aspirin in that it did not inhibit the action of
uricosuric agents. Finally, ethambutol differed
from pyrazinamide in that the hyperuricemia
due to ethambutol was not reversed by a small
dose of aspirin. Although this approach also
failed to further define the exact renal effect of
ethambutol, it appears from these studies that
ethambutol differs from each of the four classes
of agents which have been shown to decrease
the renal clearance of uric acid.
Although ethambutol-induced hyperuricemia
was not associated with the development of
acute gouty arthritis, it is clear that the hyperuricemic effect of ethambutol can be readily
reversed by the administration of sulfinpyra-
Arthritis and Rheumatism,Vol. 15. No. 4 (July-August 1972)
ETHAMBUTOL-INDUCED HYPERURICEMIA
Table 6. Characteristics of Drugs Which Produce Hyperuricemia by
Altering the Renal Handling of Uric Acid
Drugs
~~
Properties
Diuretics
Ethanol
Pyrazinarnide
~~
Salicylates
(low dose)
Ethambutol
____
Lactic acid
accumulation
ECF volume depletion
Reversal by low dose
sa Iicylates
Inhibits effect of
uricosurics
+
-
Indicates the drug produces the property described
Indicates the drug does not produce (or is not known to produce) the property described
zone, probenecid (data not shown) or allopurinol.
ACKNOWLEDGMENTS
We appreciate the technical assistance of Mrs. Margaret
C. Evans.
REFERENCES
1 . Postlethwaite AE, Bartel AG, Kelley WN: Hyperuricemia due to ethambutol. N Engl J Med
(In press)
2. Liddle L, Seegmiller JE, Laster L: Enzymatic
spectrophotometric method for determination of
uric acid. J Lab Clin Med 54:903-913, 1959
3. Taussky HH: A microcolorimetric method for
determination of creatinine in urine by the Jaffe
reaction. J Biol Chem 208:853-861,1954
4. Annino JS: Creatinine, creatine and uric acid,
Clinical Chemistry, Principles and Procedures.
Third edition. Edited by JS Annino. Boston,
Little, Brown and Company, 1964, pp 174-178
5. Ohlson GF: Optimal conditions for the enzymatic determination of L-lactic acid. Clin Chem
8:l-10,1962
6. Gutman AB: Uricosuric drugs with special reference to probenecid and sulfinpyrazone. Adv
Pharmacol Chemother 4:91-142, 1966
7. Postlethwaite AE, Kelley WN: Uricosuric effect
of radiocontrast agents. A study in man of four
commonly used preparations. Ann Intern Med
741845-852,1971
8. Yu TF, Berger L, Stone DJ, et al: Effects of
pyrazinamide and pyrazinoic acid on urate
clearance and other discrete renal functions.
Proc SOCExp Biol Med 96:264-267, 1957
9. Petty
Dalrymple ":
Inhibition Of pyrazinamide hyperuricemia by small doses of acetylsalicylic acid. Ann Intern Med 60:898-900,
1964
10. Gutman AB, Yu TF, Berger L: Renal function
in gout. 111. Estimation of tubular secretion and
reabsorption of uric acid by use of pyrazinamide
(pyrazinoic acid). Am J Med 47:575-591, 1969
1 1. Fanelli G M Jr, Bohn D, Stafford S: Functional
characteristics of renal urate transport in the
Cebus monkey. Am J Physiol 218:627-636,
1970
12. Steele T H , Oppenheimer S: Factors affecting
urate excretion following diuretic administration
in man. Am J Med 47:564-574, 1969
13. Yu TF, Gutman AB: Study of the paradoxical
effects of salicylate in low, intermediate and high
dosage on the renal mechanisms for excretion of
urate in man. J Clin Invest 38:1298-1315, 1959
14. Lieber CS, Jones DP, Losowsky MS, et al: Interrelation of uric acid and ethanol metabolism
in man. J Clin Invest 41:1863-1870,1962
15. Schirmeister J, Mau NK, Hallaner W: Study on
renal and extrarenal factors involved in the hyperuricemia induced by furosemide, Progress in
Nephrology. Edited by G Peters, F RachRamel. Berlin, Springer-Verlag Inc, 1969, p 59
Arthritis and Rheumatism, Vol. 15, No. 4 (July-August 1972)
TLj
409
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