Journal of Antimicrobial Chemotherapy (1977) 3, 585-592
Kidney transport of cefazolin in normal and impaired renal function
E. K. Brodwall T. Bergan and O. 0rjavik
Intramuscular doses of 0-5 g cefazolin were given to 17 patients with varying degrees of reduced renal function. Urinary concentrations of cefazolin were only appreciably reduced below glomerular filtration rates of 30 ml/min. During the first 12 h, 85±11% of the dose appeared in the urine in active form. The protein binding was 86±2% and was not reduced with renal function down to 10 ml/min. Cefazolin is excreted both by glomerular filtration and secretion through the tubular epithelial cells. Tubular secretion amounts to 50 to 80% of the active compound excreted down to an inulin clearance of 25 ml/min. Introduction
The elimination of cefazolin from the body is markedly dependant on the renal function (Bergan, Brodwell & 0rjavik, 1977; Craig, Welling, Jackson & Konin, 1973). The present paper deals with the urinary recovery and the renal handling of cefazolin in patients with normal and impaired renal function. Materials and methods Investigation protocol
Seventeen hospitalized patients with various degrees of renal functional impairment (Bergan et al, 1977; Craig et al, 1973) have been studied. The patients were given 500 mg cefazolin intramuscularly and no concomitant antibiotic medication was given. Urine samples were collected at 0 to 3, 3 to 4, 4 to 8, 8 to 12 and 12 to 14 h. The urine was kept at 4°C during the collection and a 100 ml sample from each collection period was kept at — 70°C until assayed. Assays. The microbiological assay has been described previously (Bergan et al., 1977). The diluent used was Sorensen's phosphate buffer pH 70. Serum protein binding was determined by a polyvinyl diffusion chamber with 3-ml wells on each side of a dialysis membrane. The chambers were filled individually, bubbled through with CO2 to saturation, and sealed. One chamber contained the serum specimen, the other a buffer consisting of Krebs-Ringer-lactate. Diffusion took place for 6 h at ambient temperature under careful agitation. 585
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
Medical Department B, Rikshospitalet and University of Oslo and Department of Microbiology, Institute of Pharmacy, University of Oslo, Oslo, Norway
586
E. K. Brodwall, T. Bergan and O. Orjavik
Parameters of renalfunction. Glomerular filtration rate was determined as clearance of inulin (Cj) and endogenous creatinine clearance (CCR) while effective plasma flow was estimated as clearance pf/>-aminohippuric acid (C P A H ). Inulin was determined after the method of Schreiner (1950) and /?-aminohippuric acid after the method of Finkelstein, Aliminosa & Smith (1941). All clearance parameters were corrected to a body surface of 1-73 m 2 and the values given on the means of 2 to 3 clearance periods. Calculation. The calculations of glomerular filtration and tubular transport followed a model used previously (Bergan, Brodwall & 0yri, 1971). The protein binding used in the calculations was 87%. The renal elimination constant (kT), and the renal clearance of cefazolin were calculated as follows: Mvf k
(0
(iii) ktxVx60
""'
1 7 73 3
_cuxvux60 c8 (l-p)
X
Tubular transport=C COTI ,
1-73x10000 167-2xWxH v 73—Cl
(V)
(vi)
where: kt = the constant for renal elimination MM' = the amount recovered in the urine during / h V = distribution volume _
X> Fxk2
Dose Serum curve area till infinity x elimination constant
F' = area under serum concentration-time curve during time t D = dose of cefazolin k2 = total elimination constant C/ tot = total clearance Clcon, x. 73= clearance corrected for protein binding and a surface area of 1 -73 m 2 cD = urine concentration during collection period, here the 60 min period between 3 and 4 h vu = urine volume during collection period, cs = the serum concentration midpoint during collection period, here in the specimen withdrawn at 3-5 h p = protein binding W = body weight (kg) H = body weight (cm).
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
GO
Renal transport of cefazolin
587
Table I. Urinary recovery of cefazolin (concentration/urine volume—ng/ml : ml) per collection interval Patent no.
0-3
1 2 3 4 5 6 7 8
3-4
9 10 11 12 13 14 15 16 17 ND=Not done;
160/80 460/248 150/583 478/270 500/29 490/184 NM 515/170 ND 564/186 380/320 570/54 340/140 500/62 320/46-5 333/48 550/2-3
59/915 295/235 25/198 110/333 92/90 78/588 33/1100 18-5/935 ND 173/332-5 85/355 ND 98/148 73/119 98/64 41-5/80 205/2-4
180/135 168/79 ND 46/56 240/203 210/97 NM 150/220 ND 495/80 635/126 965/27 165/199 530/50 141/79 590/51 NM
12-24 ND 150/57 ND ND ND ND NM ND ND 945/27 1140/41 1720/20 820/90 1332/35 825/40 844/70 NM
NM=not measurable. Results
Urine concentrations
The urinary levels are shown in Table I. The concentrations, as the data indicate, vary with the urine volume. Appreciably reduced concentrations were, however, only found in patients with glomerular filtration rate below 30 ml/min. The concentrations in the pooled specimens were mostly above 200 ug/ml during the first 8 h. Table n . Cumulative recovery of cefazolin in urine (%) Patient
0-3
3-4
4-8
8-12
12-24
1 2 3 4 5 6 7 8 10 11 13 14 15 16 17
65-7 501 65-7 32-8 42-8 42-3 710 1-6 34-6 19-7 5-5 5-4 1-3 39 0-49
670 640 66-7 401 59-4 51-5 78-3 5-0 461 25-7 8-4 71 2-5 4-5 0-58
84-2 86-8 84-2 65-9 890 69-5
89-5 — 66-4 98-8 73-6
90-3 — —
22-5 670 501 17-9 13-3 5-5 7-7 0-84
291 750 661 24-5 18 6 7-7 13-7 109
%Mum is total amount calculated to be excreted. ( % M « = T - ' ' 100)
801 75-4 37-3 23-9 14-3 25-5 —
81-2 90-4 85-8 690 97-8 73-6 400 80-4 76-8 52-8 37-7 210 39-3 2-9
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
811/170 257/975 876/375 854/192 456/410 344/615 153/2320 208/37-5 267/57 576/300 352/280 ND 425/65 277/97 255/25 205/94 511/4-8
8-12
4-8
E. K. Brodwall, T. Bergan and O. Orjavik
588
Table m . Protein binding of cefazolin in patients with various renal functions
Patient
Inulin clearance (ml/min)
Protein binding
1 3 4 5 7 9 15 16 17
147 134 125 92 53 48 17 14 10
870 89-6 86-8 84-3 89-2 881 84-7 85-9 86-2
Normal, pooled human serum
Table IV. Glomerular and tubular excretion capacity at different renal functions
Patient
%k'
c/lo,
463-5 615-6 33-8 224-9 302-4 513-9 194-2 611
421-8 677-2 31-8 2271 338-7 431-7 172-8 51-32
316-78 86-3 76-3 469-6 100-2 296-4 44-4 99-9 69-6 210-4 83-2 427-5 72-7 141-2 121 19-8
446-9 86-2
4201 79-3
3603 4314
80-6 500
32-21 10-49 4-97 5-43 0-85
56-3 36-8 22-6 63-7 58-9
c,
1 2 3 4 5 6 7 8
147 146 134 125 92 89 53 49
741 778 374 726 317 767 247 174
0-231 0-255 0-621 0-291 0-293 0-665
33-2 904 860 691 97-8 73-6
0-447
40-9
60-3 800 4-4 29-2 39-3 66-8 25-2 7-94
10 11
48 43
322 336
0194 0145
80-4 76-8
5-81 11-2
13 14 15 16 17
25 18 17 14 10
93 194 34 42 35
0028 0023 0010 0017 00012
52-8 37-7 210 39-3 2-88
7-44 3-70 2-86 111 019
C, CPAH k, °/Jc, C/,ot Clear,
= = = = = =
Cl,
=
Tubular transport (ml/min) (%)
k,
CpAH
C/corr
57-2 28-5 220 8-53 1-46
a,
51-48 29-4 22-9 818 1-39
inulin clearance (ml/min). para-aminohippuric acid (ml/min) rate constant of renal elimination (h~') per cent k, of total elimination. total body clearance (ml/min). corrected renal clearance based on C/l01, corrected for protein binding and normalized to 1-73 m1 body surface. renal clearance of cefazolin based on excretion during the period 3 to 4 h after drug administration.
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
86-9 1-84 88-6
Mean S.D.
Renal transport of cefezolin
589
Renal excretion The cumulative recovery of active cefazolin is shown in Table II. In patients with a glomerular filtration rate above 90 ml/min 84-8±10-8% of the dose was excreted in the course of the first 12 h. In patients with impaired renal function, the amount excreted was reduced. Protein binding The protein binding of cefazolin is presented in Table III. The mean protein binding in the 9 subjects studied was 86±l-8%. In a pooled serum specimen from healthy blood donors 88-6 % of adjusted cefazolin was protein bound. As will be seen from our data, there was no evidence of a reduction in protein binding with significantly reduced renal function. None of our patients were in the terminal uraemic phase.
1000-
2 3
5 7 10 20 30 50 70 100 200 Cl (ml/min)
Figure 1. Relationship between the corrected clearance of cefazolin, C/M, and glomerular filtration as assessed by inulin clearance, C,. Regression: In CVCI=—2-38+1-79 In C,; r=0-91; P
Kidney transport of cefazolin in normal and impaired renal function
E. K. Brodwall T. Bergan and O. 0rjavik
Intramuscular doses of 0-5 g cefazolin were given to 17 patients with varying degrees of reduced renal function. Urinary concentrations of cefazolin were only appreciably reduced below glomerular filtration rates of 30 ml/min. During the first 12 h, 85±11% of the dose appeared in the urine in active form. The protein binding was 86±2% and was not reduced with renal function down to 10 ml/min. Cefazolin is excreted both by glomerular filtration and secretion through the tubular epithelial cells. Tubular secretion amounts to 50 to 80% of the active compound excreted down to an inulin clearance of 25 ml/min. Introduction
The elimination of cefazolin from the body is markedly dependant on the renal function (Bergan, Brodwell & 0rjavik, 1977; Craig, Welling, Jackson & Konin, 1973). The present paper deals with the urinary recovery and the renal handling of cefazolin in patients with normal and impaired renal function. Materials and methods Investigation protocol
Seventeen hospitalized patients with various degrees of renal functional impairment (Bergan et al, 1977; Craig et al, 1973) have been studied. The patients were given 500 mg cefazolin intramuscularly and no concomitant antibiotic medication was given. Urine samples were collected at 0 to 3, 3 to 4, 4 to 8, 8 to 12 and 12 to 14 h. The urine was kept at 4°C during the collection and a 100 ml sample from each collection period was kept at — 70°C until assayed. Assays. The microbiological assay has been described previously (Bergan et al., 1977). The diluent used was Sorensen's phosphate buffer pH 70. Serum protein binding was determined by a polyvinyl diffusion chamber with 3-ml wells on each side of a dialysis membrane. The chambers were filled individually, bubbled through with CO2 to saturation, and sealed. One chamber contained the serum specimen, the other a buffer consisting of Krebs-Ringer-lactate. Diffusion took place for 6 h at ambient temperature under careful agitation. 585
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
Medical Department B, Rikshospitalet and University of Oslo and Department of Microbiology, Institute of Pharmacy, University of Oslo, Oslo, Norway
586
E. K. Brodwall, T. Bergan and O. Orjavik
Parameters of renalfunction. Glomerular filtration rate was determined as clearance of inulin (Cj) and endogenous creatinine clearance (CCR) while effective plasma flow was estimated as clearance pf/>-aminohippuric acid (C P A H ). Inulin was determined after the method of Schreiner (1950) and /?-aminohippuric acid after the method of Finkelstein, Aliminosa & Smith (1941). All clearance parameters were corrected to a body surface of 1-73 m 2 and the values given on the means of 2 to 3 clearance periods. Calculation. The calculations of glomerular filtration and tubular transport followed a model used previously (Bergan, Brodwall & 0yri, 1971). The protein binding used in the calculations was 87%. The renal elimination constant (kT), and the renal clearance of cefazolin were calculated as follows: Mvf k
(0
(iii) ktxVx60
""'
1 7 73 3
_cuxvux60 c8 (l-p)
X
Tubular transport=C COTI ,
1-73x10000 167-2xWxH v 73—Cl
(V)
(vi)
where: kt = the constant for renal elimination MM' = the amount recovered in the urine during / h V = distribution volume _
X> Fxk2
Dose Serum curve area till infinity x elimination constant
F' = area under serum concentration-time curve during time t D = dose of cefazolin k2 = total elimination constant C/ tot = total clearance Clcon, x. 73= clearance corrected for protein binding and a surface area of 1 -73 m 2 cD = urine concentration during collection period, here the 60 min period between 3 and 4 h vu = urine volume during collection period, cs = the serum concentration midpoint during collection period, here in the specimen withdrawn at 3-5 h p = protein binding W = body weight (kg) H = body weight (cm).
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
GO
Renal transport of cefazolin
587
Table I. Urinary recovery of cefazolin (concentration/urine volume—ng/ml : ml) per collection interval Patent no.
0-3
1 2 3 4 5 6 7 8
3-4
9 10 11 12 13 14 15 16 17 ND=Not done;
160/80 460/248 150/583 478/270 500/29 490/184 NM 515/170 ND 564/186 380/320 570/54 340/140 500/62 320/46-5 333/48 550/2-3
59/915 295/235 25/198 110/333 92/90 78/588 33/1100 18-5/935 ND 173/332-5 85/355 ND 98/148 73/119 98/64 41-5/80 205/2-4
180/135 168/79 ND 46/56 240/203 210/97 NM 150/220 ND 495/80 635/126 965/27 165/199 530/50 141/79 590/51 NM
12-24 ND 150/57 ND ND ND ND NM ND ND 945/27 1140/41 1720/20 820/90 1332/35 825/40 844/70 NM
NM=not measurable. Results
Urine concentrations
The urinary levels are shown in Table I. The concentrations, as the data indicate, vary with the urine volume. Appreciably reduced concentrations were, however, only found in patients with glomerular filtration rate below 30 ml/min. The concentrations in the pooled specimens were mostly above 200 ug/ml during the first 8 h. Table n . Cumulative recovery of cefazolin in urine (%) Patient
0-3
3-4
4-8
8-12
12-24
1 2 3 4 5 6 7 8 10 11 13 14 15 16 17
65-7 501 65-7 32-8 42-8 42-3 710 1-6 34-6 19-7 5-5 5-4 1-3 39 0-49
670 640 66-7 401 59-4 51-5 78-3 5-0 461 25-7 8-4 71 2-5 4-5 0-58
84-2 86-8 84-2 65-9 890 69-5
89-5 — 66-4 98-8 73-6
90-3 — —
22-5 670 501 17-9 13-3 5-5 7-7 0-84
291 750 661 24-5 18 6 7-7 13-7 109
%Mum is total amount calculated to be excreted. ( % M « = T - ' ' 100)
801 75-4 37-3 23-9 14-3 25-5 —
81-2 90-4 85-8 690 97-8 73-6 400 80-4 76-8 52-8 37-7 210 39-3 2-9
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
811/170 257/975 876/375 854/192 456/410 344/615 153/2320 208/37-5 267/57 576/300 352/280 ND 425/65 277/97 255/25 205/94 511/4-8
8-12
4-8
E. K. Brodwall, T. Bergan and O. Orjavik
588
Table m . Protein binding of cefazolin in patients with various renal functions
Patient
Inulin clearance (ml/min)
Protein binding
1 3 4 5 7 9 15 16 17
147 134 125 92 53 48 17 14 10
870 89-6 86-8 84-3 89-2 881 84-7 85-9 86-2
Normal, pooled human serum
Table IV. Glomerular and tubular excretion capacity at different renal functions
Patient
%k'
c/lo,
463-5 615-6 33-8 224-9 302-4 513-9 194-2 611
421-8 677-2 31-8 2271 338-7 431-7 172-8 51-32
316-78 86-3 76-3 469-6 100-2 296-4 44-4 99-9 69-6 210-4 83-2 427-5 72-7 141-2 121 19-8
446-9 86-2
4201 79-3
3603 4314
80-6 500
32-21 10-49 4-97 5-43 0-85
56-3 36-8 22-6 63-7 58-9
c,
1 2 3 4 5 6 7 8
147 146 134 125 92 89 53 49
741 778 374 726 317 767 247 174
0-231 0-255 0-621 0-291 0-293 0-665
33-2 904 860 691 97-8 73-6
0-447
40-9
60-3 800 4-4 29-2 39-3 66-8 25-2 7-94
10 11
48 43
322 336
0194 0145
80-4 76-8
5-81 11-2
13 14 15 16 17
25 18 17 14 10
93 194 34 42 35
0028 0023 0010 0017 00012
52-8 37-7 210 39-3 2-88
7-44 3-70 2-86 111 019
C, CPAH k, °/Jc, C/,ot Clear,
= = = = = =
Cl,
=
Tubular transport (ml/min) (%)
k,
CpAH
C/corr
57-2 28-5 220 8-53 1-46
a,
51-48 29-4 22-9 818 1-39
inulin clearance (ml/min). para-aminohippuric acid (ml/min) rate constant of renal elimination (h~') per cent k, of total elimination. total body clearance (ml/min). corrected renal clearance based on C/l01, corrected for protein binding and normalized to 1-73 m1 body surface. renal clearance of cefazolin based on excretion during the period 3 to 4 h after drug administration.
Downloaded from http://jac.oxfordjournals.org/ at Fudan University on May 4, 2015
86-9 1-84 88-6
Mean S.D.
Renal transport of cefezolin
589
Renal excretion The cumulative recovery of active cefazolin is shown in Table II. In patients with a glomerular filtration rate above 90 ml/min 84-8±10-8% of the dose was excreted in the course of the first 12 h. In patients with impaired renal function, the amount excreted was reduced. Protein binding The protein binding of cefazolin is presented in Table III. The mean protein binding in the 9 subjects studied was 86±l-8%. In a pooled serum specimen from healthy blood donors 88-6 % of adjusted cefazolin was protein bound. As will be seen from our data, there was no evidence of a reduction in protein binding with significantly reduced renal function. None of our patients were in the terminal uraemic phase.
1000-
2 3
5 7 10 20 30 50 70 100 200 Cl (ml/min)
Figure 1. Relationship between the corrected clearance of cefazolin, C/M, and glomerular filtration as assessed by inulin clearance, C,. Regression: In CVCI=—2-38+1-79 In C,; r=0-91; P
