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A BaS T R A C T The acute effects of intravenous (i.v.) but has been difficult to study in man. After the demonprobenecid and chlorothiazide on renal urate handling stration that pyrazinamide (PZA)' and pyrazinoic acid
were investigated in paired studies in normal men. are potent and highly selective inhibitors of the renal
Uricosuric responses to these agents were compared in tubular secretion of urate in several species (1-3),
the same subjects, both without and with pyrazinamide PZA subsequently was utilized to give a rough quanti(PZA) pretreatment. Assuming that PZA selectively tative estimate of the relative magnitudes of urate reabinhibits the tubular secretion of urate and that uricosuric sorption and secretion in man (4, 5). In the "PZA supagents act by increasing the excretion of filtered urate, pression test," the decrement in uric acid excretion prothen the uricosuric responses (the increment in urate duced by a maximally antiuricosuric dose of PZA is
excretion or clearance) should have been unaffected by taken as an index of tubular secretion, while the residual
PZA. Defined in this manner, however, uricosuric re- amount of urinary urate after PZA usually is considered
sponses to probenecid and chlorothiazide were signifi- to represent urinary uric acid derived from glomerular
cantly decreased after PZA pretreatment. In order to filtration but escaping tubular reabsorption (6). This
determine whether PZA diminished other renal actions interpretation depends on the assumptions that: (a) PZA
of chlorothiazide, changes in sodium and inorganic phos- completely and specifically inhibits urate secretion, and
phorus excretion were examined. Chlorothiazide pro- (b) there is no interaction between urate secretion and
duced equivalent natriuretic and phosphaturic responses reabsorption within the nephron. If the action of PZA
after PZA pretreatment, indicating that PZA does not were incomplete or nonspecific, or if a portion of the
interfere with at least some of the renal actions of secreted urate subsequently were reabsorbed, the PZA
chlorothiazide. In separate studies, PZA depressed urate technique would underestimate both tubular secretion
excretion by at least 68% during the maintenance of and reabsorption.
chlorothiazide-induced natriuresis and phosphaturia, sugThe present studies were designed to further examine
gesting that chlorothiazide does not diminish the anti- changes in renal urate handling in man during the urisecretory action of PZA.
cosuric states immediately after the administration of
The results suggest that probenecid and chlorothiazide probenecid and chlorothiazide. The increased uric acid
may derive their uricosuric properties by facilitating the excretion caused by uricosuric agents usually has been
excretion of both filtered and secreted urate. Possibly, attributed solely to an increase in the fraction of filtered
increased excretion of secreted urate might occur urate excreted. In contrast, the results of the present
through modulation of urate reabsorption at a site studies indirectly suggest that the increased excretion
distal to tubular secretion, rather than by the direct of secreted urate may contribute importantly to the uriacceleration of secretory transport. However, PZA-in- cosuric properties of probenecid and chlorothiazide.
duced interference with the actions of probenecid and
chlorothiazide on renal urate transport mechanisms canMETHODS
not be excluded as a possible explanation for the present 38 renal clearance studies were performed in 21 volunteers.
results.
All had been fully informed of the experimental nature of
the studies and gave their informed consent. None had
a history of gout. 19 subjects were normal males whose
INTRODUCTION
ages ranged from 20 to 35 yr. One female participant, R. O.,
age 54, had essential hypertension; while the other, J. S., age
The mechanism of action of uricosuric agents has been 46, had bilateral renal artery stenosis.
a matter of considerable theoretical and practical interest,
'Abbreviations used in this paper: Cinuiln, clearance of
Received for publication 2 October 1972 and in revised inulin; GFR, glomerular filtration rate; PAH, para-aminoform 23 January 1973.
hippuric; PZA, pyrazinamide.
1368
TABLE I
Responses to Probenecid,
UurateV
UurateV/
Cinulin
X 100
'Pg/min
pg/100 ml
O., control
607
444
probenecid
E. L., control
1,675
196
probenecid
probenecid
825
1,016
2,053
1,162
142
549
842
1,815
G. R., control
731
531
probenecid
1,460
1,495
J.
Curate/
UurateV/
Curate/
CinuIin
CinuIin
CinuIin
X 1OO
X100
Cinulin
pg/min Ag/100 ml
132
92
506
692
54
84
%
1.5
7.8
2.0
ml/min
11.3
9.2
11.1
ml/min
144
137
156
347
270
382
8.4
4.8
7.0
1.1
3.5
1.2
5.4
0.8
4.3
1.4
4.9
1.8
9.0
14.6
3.4
7.2
5.7
7.7
3.0
15.0
8.4
10.5
12.3
11.1
154
110
107
(0.5)
(1.1)
5.9
(.7)
7.3
(1.3)
(7)
118
(8)
NS
<0.02
X 1OO
%
10.0
Cinulin
ml/min ml/min
9.0
28.2
4.8
12.4
7.4
20.8
10.2
138
144
147
UurateV
H. A., control
382
316
18.8
10.1
29.1
6.8
probenecid
H. O., control
1,827
1,428
26.4
688
2,459
895
2,120
645
(107)
1,774
(200)
392
1,889
591
1,817
465
(84)
1,451
(180)
6.3
31.2
10.2
33.4
8.3
13.0
14.1
14.4
13.5
6.6
5.6
4.2
14.0
12.5
16.1
9.9
11.4
(0.9)
(1.5)
26.8
(2.1)
10.4
(1.4)
(6)
126
(7)
192
66
257
64
285
70
240
108
(29)
342
(63)
<0.001
<0.001
<0.001
NS
NS
<0.01
G. U., control
probenecid
G. O., control
probenecid
Control-mean
(SEM)
Probenecid-mean
(SEM)
P
150
121
113
133
98
111
130
158
127
122
117
133
68
226
246
360
62
187
63
280
49
249
59
207
89
(27)
288
(42)
<0.05
<0.001
111
103
105
95
128
114
117
116
124
Control, mean of control periods; Probenecid, mean of periods during the hour after probenecid; 500 mg i.v.; UuratV, urate excretion
rate; Cinulnn inulin clearance (GFR); Curate/Ciuin, urate-to-inulin clearance ratio, V, urine flow, NS, P > 0.05.
RESULTS
Uricosuric responses to probenecid, 500 mg i.v., were
measured in paired experiments in seven normal men
in the same participants, except that each received PZA, 3 g without and with PZA pretreatment (Table I). Without
orally, 90 min before onset of the control periods for the PZA, urate excretion averaged 645+107 eg/min (mean
second study. In four other studies with chlorothiazide, par- SEM) in control periods and increased by a mean of
ticipants received 3 g of PZA orally after completion of 1,129150 /g/min after probenecid. When the same indithe above experimental sequence without PZA. The format
PZA pretreatment, control
then was repeated, beginning with infusion of 1,000 ml viduals were restudied after
of 0.45% NaCI during another equilibration interval, during urate excretion values averaged 10829 Ag/min, but
probenecid increased urate excretion by only 23558
which the antiuricosuric action of PZA developed.
1369
500
!p0
15
~~~~~ROENCID
-]
to
500-
o:
I--
0O
W0
w2
5-
25
20
.5
6(84 1)
15-
600
CHLOROTHIAZIDE
60
'I
.s400-4
--
200-
10
p~\
0-
WITH
PZA
WITHOUT
WITH
PZA
PZA
FIGURE 2 Changes
in
(ACurate/Cinul In) after probenecid or chlorothiazide. Probenecid and chlorothiazide produced significantly smaller
changes in Curate/Cinu. 1 after PZA pretreatment (P
<0.02). Plasma urate concentrations were not significantly
different in the paired studies.
TABLE I I
Uricosuric:Responses to Chlorothiazide, Without and With PZA Pretreatment
With pretreatment
C. O., control
chlorothiazide
F. E., control
chlorothiazide
H. L., control
chlorothiazide
Z. O., control
chlorothiazide
V. O., control
chlorothiazide
H. F., control
chlorothiazide
S. A., control
chlorothiazide
E. L., control
chlorothiazide
M. A., control
chlorothiazide
C. V., control
chlorothiazide
Control-mean
(SEM)
Chlorothiazide-mean
(SEM)
P
UurateV/
Curate/
UurmteV/
Curate/
Cinulin
X100
Cinulin
Cinulin
Uuratev
Cinulin
X100
X 100
X100
Cinulin
Ag/min
pg/100 ml
ml/min
ml/min
1.3
5.9
1.2
3.9
1.7
8.0
0.45
1.4
2.3
7.3
9.1
19.7
26.9
10.1
16.1
14.8
9.6
15.8
17.8
14.5
495
1,037
600
1,023
446
799
535
1,086
530
1,200
553
865
453
869
443
732
512
1,159
719
942
529
(27)
971
(49)
<0.001
406
749
462
931
504
869
361
926
392
1,007
385
1,226
380
860
413
810
407
643
577
922
429
(21)
894
(49)
<0.001
%
7.0
12.8
7.2
15.2
9.5
17.1
5.8
14.7
8.9
23.4
8.0
25.7
6.7
16.8
9.8
19.8
7.5
12.6
11.6
19.3
8.2
(0.6)
17.7
(1.4)
<0.001
Cinulin
ml/min ml/min
7.6
10.3
11.6
21.9
6.3
8.9
12.1
9.6
15.7
15.1
20.1
12.2
13.8
12.4
13.3
19.8
10.9
17.5
8.5
19.9
12.0
(1.3)
14.8
(1.5)
NS
122
135
130
107
88
92
148
122
139
119
152
90
119
101
110
101
126
150
129
107
126
(6)
112
(6)
NS
UurateV
psg/min ,ug/100 ml
109
480
127
305
95
392
45
117
159
525
147
378
78
360
38
268
186
779
208
658
119
(18)
426
(61)
<0.001
91
412
81
257
75
349
31
104
111
428
155
318
67
340
30
271
141
404
159
554
92
(14)
319
(43)
<0.001
9.6
2.8
5.7
1.1
5.7
0.75
6.8
2.4
7.3
3.6
12.7
1.8
(0.3)
6.7
(1.0)
<0.001
14.2
9.9
24.8
17.8
19.6
14.0
19.1
17.8
21.7
14.2
(1.3)
17.9
(1.9)
NS
Studies and abbreviations are similar to Table I, except that chlorothiazide, 500 mg, was administered instead of probenecid.
1370
120
107
175
119
128
113
144
116
142
121
94
112
117
110
133
100
133
139
132
114
132
(7)
115
(3)
<0.05
TABLE I I I
Plasma Solute Concentrations in Paired Experiments*
Probenecid studies
Without PZA
(7 studies)
With PZA
(7 studies)
Chlorothiazide studies
Without PZA
(10 studies)
With PZA
(10 studies)
Plasma
urate
Plasma
sodium
Plasma
phosphorus
mg/100 ml
meq/liter
mg/1OG ml
5.4
(0.7)
5.1
(0.5)
138
(1)
141
(1)
2.6
(0.1)
2.7
(0.1)
5.3
(0.2)
5.6
(0.4)
140
(1)
142
(1)
2.7
(0.1)
2.7
(0.1)
1371
8-
A CNa /C inulin
(X 100)
64-
2-
201
A C phosphate /Cinulin 3
(x 100)
10-
WITHOUT
PZA
WITH
PZA
TABLE V
x100
P. R., Control
First chlorothiazide peak
PZA peak
Second chlorothiazide peak
S. T., control
First chlorothiazide peak
PZA peak
Second chlorothiazide peak
J. S., control
First chlorothiazide peak
PZA peak
Second chlorothiazide peak
R. O., control
First chlorothiazide peak
PZA
Second chlorothiazide peak
C urate/
Cinulin
x100
Cphosphate/
V/Cinulin
x100
CN./Cinulin
x1too
Cinulin
xio
Ag/100 ml
461
10.8
23.5
12.1
19.2
15.0
13.9
8.4
10.1
4.4
9.1
0.66
5.72
4.54
7.65
0.77
3.19
3.06
5.65
1.7
11.6
5.8
12.4
3.04
9.6
22.8
25.6
27.8
16.1
24.8
30.1
42.0
9.5
24.2
19.4
27.8
5.3
9.11
6.19
11.1
8.3
8.47
9.7
1,568
145
342
363
880
86
575
374
951
99
263
444
973
43
150
2.4
5.8
5.1
13.0
1.5
9.7
9.9
24.4
2.3
6.4
11.4
24.4
1.1
3.3
7.3
9.4
8.7
14.4
8.5
11.1
15.2
11.9
Control, mean values during control periods; First chlorothiazide peak, values during peak uricosuric
action of first dose of chlorothiazide; 500 mg i.v.,; PZA peak, values during peak antiuricosuric action
of PZA (between 60 and 120 min after administration of PZA, 3 g.p.o.); Second chlorothiazide peak,
values during peak uricosuric effect of second dose of chlorothiazide, 500 mg i.v., administered 120 min
after PZA. Subjects received 1,000 ml 0.45% NaCl during the hour preceding the onset of control
periods and during the 1st h after PZA administration.
1372
1373
(30).
The data also are consistent with a diminished response to uricosuric agents in hyposecretory stateseither induced pharmacologically or by disease. If diuretic-induced hyperuricemia is due partially to diminished
net urate secretion (24), the uricosuric response to
probenecid might be subnormal in that condition. Although previous data have suggested that probenecid is
effective at ameliorating chronic diuretic-inducing hyperuricemia, no comparisons of uricosuric responses in
normals and hyperuricemic patients were made (31).
In far advanced chronic renal disease, net urate secretion per nephron usually appears to be severely compromised, as judged by the PZA suppression test (32).
The increased fraction of filtered urate excreted (after
PZA) suggests that reabsorption also is impaired. In
chronic lead nephropathy, however, PZA suppression
1374
ACKNOWLEDGMENTS
These studies were supported by U. S. Public Health Service Research Grant 1-RO1-AM15162, U. S. Public Health
Service Program Grants 1-PO1-AM15512 and 2-PO2-AM05630, and by a grant from the Wisconsin Heart Association.
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