Depression of renal clearance of furosemide in man by azotemia The renal clearance of furosemide and tetraethylammonium (TEA) were compared in 10 patients with hypertensive nephropathy. BUN and creatinine ranges were 10 to 88 mgldl and 0.9 to 3.8 mgldl, respectively. Diuretics were discontinued 48 hr prior to the study, and 2 consecutive clearances (mI/mini 1.73 m 2BSA) of creatinine were performed. The patient then received a bolus followed by a constant infusion of furosemide- l 4C and tetraethylammonium- l 4C (analyzed by specijic methodology for plasma and urine), both in subpharmacologic doses. After 40-min equilibration sequential 20-min clearance periods were obtained. Both the clearance of furosemide (range 17 to 133) and TEA (range 99 to 443) correlated negatively with BUN and serum creatinine and positively with creatinine and urea clearances. Thus, by using a constant-injusion technique we demonstrated that the renal clearance of furosemide is depressed by azotemia in man and that there was greater depression with furosemide than with TEA.
H. Josephine Rose, M.D., Kevin O'Malley, M.D., Ph.D.,* and Albert W. Pruitt, M.D. Atlanta, Ga.
Departments of Pediatrics, Medicine, and Pharmacology and the Clinical Pharmacology Program, Emory University School of Medicine
Furosemide is an effective diuretic in renal disease, but as the glomerular filtration rate decreases the ability to produce a diuresis becomes more difficult.1, 12 This depression could be related to the renal tubular transport of furosemide, which is similar to that of c1assical organic acid system. 5, 8 Specifically, uremia, which inhibits the renal transport of para-
aminohippuric acid (P AH), 9, 14, 19 could also inhibit that of furosemide. Our work,15 wh ich supports this hypothesis, showed that the renal c1earance of furosemide in dogs decreased linearly with progressive azotemia. Subsequently, we demonstrated in dogs a relationship between natriuretic effect of furosemide and the urinary excretion of the drug. 16
Supported in part by United States Public Health Service Grants GM-14270, 0-001031, RR 00039 (Clinical Research Facility, Emory University), and HOO 1275 (Or. Rose). Received for publication July 6, 1976. Accepted for publication Aug. 17, 1976. Reprint requests to: Or. H. Josephine Rose, Woodruff Memorial Bldg., Emory University School of Medicine, Atlanta, Ga. 30322. *Present address: University of Oundee, Oepartment of Pharmacology and Therapeutics, Ninewells Hospital, Oundee, Scotland 0019SY.
The study reported here was designed to determine the renal c1earance of furosemide in human volunteers and to assess the effect of impaired renal function on the renal elimination of the drug. An ineffective dose of furosemide was given as a load followed by a constant infusion. In addition, the renal c1earance of furosemide was compared simultaneously with the renal transport of an organic base, tet141
142
Rose, 0' Malley, and Pruitt
Clinical Pharmacology and Therapeutics
Table I. Basie elinieal data Jor the patients Patient I T. N. 2 C. B. 3 E. H. 4 B. H. 5G. W. 6 E. E. 7 A. G. 8 M. E. 9 R. S. 10 M. F.
1
Age (yr) 44 41 43 57 55 62 53 54 42 51
I
Wt (kg) 68.0 69.0 71.4 110.5 64.5 74.0 79.7 67.0 50.5 55.7
I
Ht (em)
BSA * (m 2)*
170 158 160 169 158 152 168 142 162 154
1.78 1.70 1.74 2.19 1.66 1.71 1.89 1.56 1.51 1.52
I
MAPt (mm Hg) 106 107 118 103 101 145 105 114 99 95
I
Total protein t (albumin) (gm/dl) 7.4 (4.6) 6.9 (4.2) 6.5 (3.8) 6.9 (4.2) 7.6 (4.8) 7.1 (4.0) 7.6(4.3) 7.8 (4.6) 7.5 (4.3) 8.4 (5.0)
*BSA: body surface area. t MAP: mean arterial pressure = diastolic + 1/3 pulse pressure on study day. :j:Normal range: total protein, 6-8.0 gm/dl; albumin, 3.5-5.0 gm/dl.
raethylammonium (TEA). In animals, TEA has been shown to be unaffected by progressive azotemiall, 15; thus TEA is a reliable index of renal plasma ftow over a wide range of blood urea nitrogen (BUN). We demonstrated that the renal clearance of both furosemide and TEA decreased with progressive azotemia in man and that there was greater depression of the renal clearance of furosemide. Patients and methods
Ten female patients with essential hypertension of 3 to 20 years' duration and varying impairment of renal function were admitted to the Clinical Research Facility at Emory University Hospital. After admission, diuretics were discontinued for 48 hr, and during this time 2 consecutive 24-hr creatinine clearances were obtained. The patients were maintained on a 40 mEq sodium diet, and antihypertensive medications were continued. On the day of the drug clearance study, a venous heparin lock and abladder catheter were inserted. SampIes of plasma and urine were obtained for use as chemical "blanks," and urine was cultured at the beginning and end of catheterization. The patients then received an intravenous load followed by a constant infusion of furosemideßC and TEAßC. * *Furosemide, carboxyl-14C (I) Mallinckrodl (specific activity 6.49 mCi/m mole), Science Products Division, SI. Louis (6 patients), and (2) California Bionuclear Corporation (specific activity, 4.3 mCi/m mole), Sun Valley (4 patients). Tetraethyl (1- l4 C) ammonium bromide (specific activity 2.80 mCi/m mole), New England Nuclear, Boston.
The solutions were prepared as folIows: 15 to 18 ,uCi of furosemide was dissolved in 25 ml of normal saline and 20 ,uCi (0.25 mg) of TEA was diluted to 5 ml in saline. One fourth of the solutions (l ml TEA and 6 ml of furosemide) was given as the intravenous bolus. The remaining solutions were added to 500 ml of 0.45 N saline which was infused by a constant-infusion pump at 2.75 ml per minute. All solutions were administered through a disposable Millipore filter (0.22 ,u). The continuous infusion was started immediately after the bolus. Forty minutes was then allowed for equilibration. Seven sequential 20-min urine sampIes were collected and plasma was obtained at the midpoint of each collection. After 180 min, the drug infusion was discontinued and all spontaneously voided urine sampIes for the next 21 hr were collected and pooled. Each plasma and urine sampIe was assayed by specific methods for furosemide and TEA concentrations,15 which was applicable to human sampIes. The amount of furosemide and TEA excreted from 3 to 24 hr after discontinuing the drug infusion was also measured. Recovery of furosemide from plasma and urine was determined and was corrected for each patient. Recovery was always at least 97%. Basic clinical data for the patients are presented in Table I. The patients were 41 to 62 yr of age, and mean arterial pressure ranged from 95 to 145 mm Hg on the day of the study. All patients had a serum total protein and serum
Valurne 21 Nurnber 2
Furosemide clearance in azotemia
143
Table 11. Renal data Serum concentrations
Clearances (mllmin/l.73 m 2)
Patients
Urine jiow (mllmin)
Urea nitrogen (mg/dl)
Creatinine (mg/dl)
Creatinine
Urea
T. N. C. B. E. H. B. H. G.W. E. E. A. G. M. E. R. S. M. F.
3.85 2.37 0.74 3.63 1.89 2.08 1.11 2.30 1.20 1.00
10 20 12 17 26 23 44 58 47 88
0.85 1.05 1.10 1.20 1.35 1.60 1.60 1.75 3.00 3.80
89 90 96 50 56 44 44 63 26 14
51 21 48 38 20 21 14 9 11 8
Clearances (ml/min/l.73 m 2) TEA
Furosemide M* lSEM
PF UFV (ng/ml) (ng/min)
M
1
133.1 9.4 444.5 120.2 31.8 349.8 107.2 17.3 31,8.6 75.0 12.6 250.9 3.1 356.3 51.3 62.9 5.6 233.3 44.6 3.1 186.2 52.4 5.0 255.0 93.1 26.3 2.3 16.5 1.4 118.8
SEM
M
M
43.2 75.3 54.6 43.2 9.8 20.0 15.5 29.0 7.8 12.0
2.12 1.95 2.91 1.91 2.25 4.69 2.31 2.34 4.27 4.81
293 207 302 180 111 260 113 110 97 71
*M: Mean; SEM: standard error of mean; PF : plasma furosemide concentration; UF V: urine furosemide excretion.
albumin within the normal range for our laboratory. Concurrent medications other than diuretics were hydralazine, guanethidine, propran0101, and minoxidil. Patients 1 and 6 received hydralazine, propranolol, and guanethidine, Patients 7 and 8, minoxidil only, and Patients 9 and 10, minoxidil and propranolol. All clearance values are corrected to 1.73 m2 body surface area (BSA). The renal clearances of furosemide and TEA as presented are the average of 7 clearance periods. Results
Renal clearance 0/ /urosemide. The renal clearance of furosemide (CF) was studied in 10 patients as shown in Table II with the BUN ranging from 10 to 88 mg/dl. The clearance of furosemide ranged from 16.5 to 133.1 mll mini 1.73 m2 • The clearance of furosemide correlated by simple linear regression with BUN. CF
=
111.6 - 1.26 BUN, r
= 0.81,
P < 0.005(1)
It also correlated with other measurements of renal function, serum creatinine (Ser), creatinine clearance (Cer), and urea clearance (Cu). CF = 127.63 - 33.92 SC" r = 0.81, P
< 0.005
CF = 1.32 Cer - 6.71, r = 0.93, P < 0.001 CF = 20.7 + 2.00 Cu, r = 0.81, P < 0.005
(2) (3)
(4)
The plasma concentration and urinary excretion rate of furosemide during the continuous infusion ranged from 1.91 to 4.81 ng/ml and from
70.5 to 302.1 ng/min, respectively. The range of standard error of me an was 0.016 to 0.299 and 8.0 to 50.5 for plasma and urinary furosemide excretion rate, respectively. Renal clearance 0/ TEA. The renal clearance of TEA (C TEA) for the 10 patients (Table II) ranged from 93.1 to 445 mll mini 1. 73 m2 • The clearance of TEA correlated by simple linear regression with BUN. C TEA = 374.7 - 3.28 BUN, r = 0.74, (5) P < 0.02
TEA clearance also correlated with serum creatinine, creatinine clearance, and urea clearance. CTEA = 430.2 - 98.0 SeR' r = 0.84, (6) P < 0.005 CTEA = 63.8 + 3.44 Cer, r = 0.86, P < 0.005 (7) C TEA = 144.8 + 4.80 Cu, r = 0.70, P < 0.05 (8)
Recovery 0/ total radioactivity administered. Except for Patient M. F., more than 74% total radioactivity was recovered in the urine collected during the 24 hr following the administration of the drugs (in the case of Patient M. F., 56% was recovered). The me an recovery was 88.4% of the total radioactivity administered. Discussion
We have demonstrated in man that the renal clearance of two actively transported materials, furosemide and TEA, is decreased by renal im-
144
Rose, O'Malley, and Pruitt
C\I
140
E
t()
I'-
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Clinical Pharmacology and Therapeutics
500 N
•
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H. Josephine Rose, M.D., Kevin O'Malley, M.D., Ph.D.,* and Albert W. Pruitt, M.D. Atlanta, Ga.
Departments of Pediatrics, Medicine, and Pharmacology and the Clinical Pharmacology Program, Emory University School of Medicine
Furosemide is an effective diuretic in renal disease, but as the glomerular filtration rate decreases the ability to produce a diuresis becomes more difficult.1, 12 This depression could be related to the renal tubular transport of furosemide, which is similar to that of c1assical organic acid system. 5, 8 Specifically, uremia, which inhibits the renal transport of para-
aminohippuric acid (P AH), 9, 14, 19 could also inhibit that of furosemide. Our work,15 wh ich supports this hypothesis, showed that the renal c1earance of furosemide in dogs decreased linearly with progressive azotemia. Subsequently, we demonstrated in dogs a relationship between natriuretic effect of furosemide and the urinary excretion of the drug. 16
Supported in part by United States Public Health Service Grants GM-14270, 0-001031, RR 00039 (Clinical Research Facility, Emory University), and HOO 1275 (Or. Rose). Received for publication July 6, 1976. Accepted for publication Aug. 17, 1976. Reprint requests to: Or. H. Josephine Rose, Woodruff Memorial Bldg., Emory University School of Medicine, Atlanta, Ga. 30322. *Present address: University of Oundee, Oepartment of Pharmacology and Therapeutics, Ninewells Hospital, Oundee, Scotland 0019SY.
The study reported here was designed to determine the renal c1earance of furosemide in human volunteers and to assess the effect of impaired renal function on the renal elimination of the drug. An ineffective dose of furosemide was given as a load followed by a constant infusion. In addition, the renal c1earance of furosemide was compared simultaneously with the renal transport of an organic base, tet141
142
Rose, 0' Malley, and Pruitt
Clinical Pharmacology and Therapeutics
Table I. Basie elinieal data Jor the patients Patient I T. N. 2 C. B. 3 E. H. 4 B. H. 5G. W. 6 E. E. 7 A. G. 8 M. E. 9 R. S. 10 M. F.
1
Age (yr) 44 41 43 57 55 62 53 54 42 51
I
Wt (kg) 68.0 69.0 71.4 110.5 64.5 74.0 79.7 67.0 50.5 55.7
I
Ht (em)
BSA * (m 2)*
170 158 160 169 158 152 168 142 162 154
1.78 1.70 1.74 2.19 1.66 1.71 1.89 1.56 1.51 1.52
I
MAPt (mm Hg) 106 107 118 103 101 145 105 114 99 95
I
Total protein t (albumin) (gm/dl) 7.4 (4.6) 6.9 (4.2) 6.5 (3.8) 6.9 (4.2) 7.6 (4.8) 7.1 (4.0) 7.6(4.3) 7.8 (4.6) 7.5 (4.3) 8.4 (5.0)
*BSA: body surface area. t MAP: mean arterial pressure = diastolic + 1/3 pulse pressure on study day. :j:Normal range: total protein, 6-8.0 gm/dl; albumin, 3.5-5.0 gm/dl.
raethylammonium (TEA). In animals, TEA has been shown to be unaffected by progressive azotemiall, 15; thus TEA is a reliable index of renal plasma ftow over a wide range of blood urea nitrogen (BUN). We demonstrated that the renal clearance of both furosemide and TEA decreased with progressive azotemia in man and that there was greater depression of the renal clearance of furosemide. Patients and methods
Ten female patients with essential hypertension of 3 to 20 years' duration and varying impairment of renal function were admitted to the Clinical Research Facility at Emory University Hospital. After admission, diuretics were discontinued for 48 hr, and during this time 2 consecutive 24-hr creatinine clearances were obtained. The patients were maintained on a 40 mEq sodium diet, and antihypertensive medications were continued. On the day of the drug clearance study, a venous heparin lock and abladder catheter were inserted. SampIes of plasma and urine were obtained for use as chemical "blanks," and urine was cultured at the beginning and end of catheterization. The patients then received an intravenous load followed by a constant infusion of furosemideßC and TEAßC. * *Furosemide, carboxyl-14C (I) Mallinckrodl (specific activity 6.49 mCi/m mole), Science Products Division, SI. Louis (6 patients), and (2) California Bionuclear Corporation (specific activity, 4.3 mCi/m mole), Sun Valley (4 patients). Tetraethyl (1- l4 C) ammonium bromide (specific activity 2.80 mCi/m mole), New England Nuclear, Boston.
The solutions were prepared as folIows: 15 to 18 ,uCi of furosemide was dissolved in 25 ml of normal saline and 20 ,uCi (0.25 mg) of TEA was diluted to 5 ml in saline. One fourth of the solutions (l ml TEA and 6 ml of furosemide) was given as the intravenous bolus. The remaining solutions were added to 500 ml of 0.45 N saline which was infused by a constant-infusion pump at 2.75 ml per minute. All solutions were administered through a disposable Millipore filter (0.22 ,u). The continuous infusion was started immediately after the bolus. Forty minutes was then allowed for equilibration. Seven sequential 20-min urine sampIes were collected and plasma was obtained at the midpoint of each collection. After 180 min, the drug infusion was discontinued and all spontaneously voided urine sampIes for the next 21 hr were collected and pooled. Each plasma and urine sampIe was assayed by specific methods for furosemide and TEA concentrations,15 which was applicable to human sampIes. The amount of furosemide and TEA excreted from 3 to 24 hr after discontinuing the drug infusion was also measured. Recovery of furosemide from plasma and urine was determined and was corrected for each patient. Recovery was always at least 97%. Basic clinical data for the patients are presented in Table I. The patients were 41 to 62 yr of age, and mean arterial pressure ranged from 95 to 145 mm Hg on the day of the study. All patients had a serum total protein and serum
Valurne 21 Nurnber 2
Furosemide clearance in azotemia
143
Table 11. Renal data Serum concentrations
Clearances (mllmin/l.73 m 2)
Patients
Urine jiow (mllmin)
Urea nitrogen (mg/dl)
Creatinine (mg/dl)
Creatinine
Urea
T. N. C. B. E. H. B. H. G.W. E. E. A. G. M. E. R. S. M. F.
3.85 2.37 0.74 3.63 1.89 2.08 1.11 2.30 1.20 1.00
10 20 12 17 26 23 44 58 47 88
0.85 1.05 1.10 1.20 1.35 1.60 1.60 1.75 3.00 3.80
89 90 96 50 56 44 44 63 26 14
51 21 48 38 20 21 14 9 11 8
Clearances (ml/min/l.73 m 2) TEA
Furosemide M* lSEM
PF UFV (ng/ml) (ng/min)
M
1
133.1 9.4 444.5 120.2 31.8 349.8 107.2 17.3 31,8.6 75.0 12.6 250.9 3.1 356.3 51.3 62.9 5.6 233.3 44.6 3.1 186.2 52.4 5.0 255.0 93.1 26.3 2.3 16.5 1.4 118.8
SEM
M
M
43.2 75.3 54.6 43.2 9.8 20.0 15.5 29.0 7.8 12.0
2.12 1.95 2.91 1.91 2.25 4.69 2.31 2.34 4.27 4.81
293 207 302 180 111 260 113 110 97 71
*M: Mean; SEM: standard error of mean; PF : plasma furosemide concentration; UF V: urine furosemide excretion.
albumin within the normal range for our laboratory. Concurrent medications other than diuretics were hydralazine, guanethidine, propran0101, and minoxidil. Patients 1 and 6 received hydralazine, propranolol, and guanethidine, Patients 7 and 8, minoxidil only, and Patients 9 and 10, minoxidil and propranolol. All clearance values are corrected to 1.73 m2 body surface area (BSA). The renal clearances of furosemide and TEA as presented are the average of 7 clearance periods. Results
Renal clearance 0/ /urosemide. The renal clearance of furosemide (CF) was studied in 10 patients as shown in Table II with the BUN ranging from 10 to 88 mg/dl. The clearance of furosemide ranged from 16.5 to 133.1 mll mini 1.73 m2 • The clearance of furosemide correlated by simple linear regression with BUN. CF
=
111.6 - 1.26 BUN, r
= 0.81,
P < 0.005(1)
It also correlated with other measurements of renal function, serum creatinine (Ser), creatinine clearance (Cer), and urea clearance (Cu). CF = 127.63 - 33.92 SC" r = 0.81, P
< 0.005
CF = 1.32 Cer - 6.71, r = 0.93, P < 0.001 CF = 20.7 + 2.00 Cu, r = 0.81, P < 0.005
(2) (3)
(4)
The plasma concentration and urinary excretion rate of furosemide during the continuous infusion ranged from 1.91 to 4.81 ng/ml and from
70.5 to 302.1 ng/min, respectively. The range of standard error of me an was 0.016 to 0.299 and 8.0 to 50.5 for plasma and urinary furosemide excretion rate, respectively. Renal clearance 0/ TEA. The renal clearance of TEA (C TEA) for the 10 patients (Table II) ranged from 93.1 to 445 mll mini 1. 73 m2 • The clearance of TEA correlated by simple linear regression with BUN. C TEA = 374.7 - 3.28 BUN, r = 0.74, (5) P < 0.02
TEA clearance also correlated with serum creatinine, creatinine clearance, and urea clearance. CTEA = 430.2 - 98.0 SeR' r = 0.84, (6) P < 0.005 CTEA = 63.8 + 3.44 Cer, r = 0.86, P < 0.005 (7) C TEA = 144.8 + 4.80 Cu, r = 0.70, P < 0.05 (8)
Recovery 0/ total radioactivity administered. Except for Patient M. F., more than 74% total radioactivity was recovered in the urine collected during the 24 hr following the administration of the drugs (in the case of Patient M. F., 56% was recovered). The me an recovery was 88.4% of the total radioactivity administered. Discussion
We have demonstrated in man that the renal clearance of two actively transported materials, furosemide and TEA, is decreased by renal im-
144
Rose, O'Malley, and Pruitt
C\I
140
E
t()
I'-
"c E "E u..
U
•
Clinical Pharmacology and Therapeutics
500 N
•
E 400 r
