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The effect of renal cation transport inhibitors on the in vivo and in vitro accumulation and efflux of cephaloridine
Life Sciences, Vol. 27, pp. 2559-2564 Printed in the U.S.A.
Pergamon Press
THE EFFECTOF RENAL CATION TRANSPORTINHIBITORS ON THE IN VIVO AND IN VITRO ACCUMULATION ~LUX OF CE~RIDINE J. S. Wold, S. A. Turnipseed Toxicology Division L i l l y Research Laboratories Greenfield, Indiana, 46140
Summary I t has been shown that the nephrotoxicity of cephaloridine is enhanced by pre-treatment with the inhibitors of renal cation transport, cyanine or nw~piperphenidol. T h i s report describes experiments directed towards determining the mechanism of this effect. The nephrotoxicity of cephaloridine has been shown to be closely dependent upon renal cortical concentrations. Cyanine does not alter the uptake of cephaloridine either in vivo or in vitro. However, renal cortical concentrations c--e~-alori~Tne at later time points after the administration of the antibiotic are significantly higher in cyanine pre-treated animals. The efflux of cephaloridine from preloaded renal cortical slices is significantly slowed by the presence of cyanine or n~piperphenidol in the efflux media. It was concluded that cephaloridine depends on a relatively inactive but necessary cationic transport step for exit from proximal tubular cells and an inhibition of this transport results in increased cortical concentrations, particularly at later time points after the dose which would explain the enhanced nephrotoxicity observed after pretreatment with cation transport inhibitors. Cephaloridine is a broad-spectrum cephalosporin antibiotic that has been shown to produce dose-related nephrotoxicity in the rabbit and in other laboratory animals characterized by acute necrosis of the proximal renal tubules (1,2). The nephrotoxicity of cephaloridine has also been observed in man (3,4). The activity of the renal organic anion transport system has been shown to be an important determinant of the nephrotoxicity of cephaloridine in the rabbit. Inhibition of anion transport by probenecid or other organic anions, results in decreased cortical concentrations of cephaloridine and protects against cephaloridine nephrotoxicity (5,6,7,8). Immature rabbits accumulate less cephaloridine into the renal cortex and are relatively resistant to cephaloridine nephrotoxicity due to the incomplete development of the organic anion transport system (9,10). Although the anionic transport system is clearly important in the processes resulting in h i g h renal cortical concentrations and corresponding cortical tubular necrosis, cephaloridine is actually a zwitterion possessing a formal positive rharge on the quarternary 0024-3205/80/512559-06502.00/0 Copyright (c) 1980 Pergamon Press Ltd.
2560
Cephaloridine and Renal Cationic Transport
Vol. 27, No.s 25-26, 1980
nitrogen of the pyridinium substltuent on the beta lactam ring In addition to the anionic carboxyl group. Thus, the renal cation transport system may also influence the movement of cephaloridine into or out of the proximal tubular cells. We have previously examined the effect of the cyanine dye, cyanlne 863, an inhibitor of renal cation transport on cephalorldine nephrotoxicity. C y a n i n e administration specifically enhanced cephaloridine nephrotoxicity while the nephrotoxicity of cefazolin sodium or mercuric chloride were unaffected (11). T h i s report descrlbes an examination of the effect of cation transport inhibitors on the concentration of cephaloridine and other cephalosporins in renal cortex. We have examined the effect of cyanine on cephaloridine concentrations in vivo and on the uptake and efflux of cephaloridine in vitro. The result~ support the conclusion that cephalorldine depends on a cationic transport system for exit from proximal tubular cells, and that inhibition of cation transport results in prolonged concentrations of cephaloridine which are assumed to result in the enhanced nephrotoxicity observed. Methods
Adult female Dutch-belted rabbits were used for all experiments. haloridine (LORIDINE, Eli L i l l y and Company, Indianapolis, IN) and 4C cephaloridine and 14C cephalothin with the label in the carbonyl carbon of the thiophene-2-acetamido substituent at the 7 position were obtained from Eli L i l l y and Company, Indianapolis, IN. Cyanine dye, cyanine 863, 1-ethyl-2[(1,4-dimethyl-2-phenyl-6-pyrimidinylidine)-methyl] quinolinium chloride, referred to hereafter as cyanine, was obtained from Eastman Kodak Co., Rochester, N.Y. Mepiperphenidol was obtained from Dr. C. Sweet, Merck B Co., West Point, PA. 14C tetraethylammonium bromide (TEA) was obtained from New England Nuclear, Boston, Massachusetts. In vitro uptake and efflux studies were performed on thin slices of rena~ cortex through use of a Stadie-Riggs microtome (12). Incubations were carried out in 3 ml of the buffer of Cross and Taggart (13) with cephaloridine present at 3 x 10-4 M and PAH or TEA present at a concentration of 7.4 x 10-5 M. Incubations were carried out at 25°C under 100 oxygen for 90 minutes with a shaking rate of 100 cycles per minute. Radioactivity of TEA was determined in the trichloroacetic acid supernatant solutions as described previously (11). Efflux experiments using 14C cephaloridine or cephalothin w e r e also carried out as described previously in reports from this laboratory (14). All drug administration was carried out using the subcutaneous route of administration. Cephaloridine was measured in renal cortex in both in vitro and in vivo experiments through use of high pressure liqui--dchromatograph--y
~ep
Statistical analyses were carried out by use of student's t test (16) or the paired t test (17). Results Table I shows the accumulation of para-aminohippurate (PAH), tetraethyla~onium (TEA) and cephaloridine in tissue slices from non-treated animals in the presence or absence of cyanine. Table II presents similar data on tissue from animals pretreated with cyanine, 4 m~/kg or saline 30 minutes prior to sacrifice and preparation of cortical slices.
Vol. 27, No.s 25-26, 1980
Cephaloridine and Renal Cationic Transport
2561
Cyanine, as expected, had no effect on the uptake of PAH, and s i g n i f i c a n t l y reduced the slice:medium ratio of TEA. Cyanine, either present in the incubation medium or after pretreatment of the animals, had no effect on the renal cortical accumulation of cephaloridine. The effect of mepiperphenidol and cyanine on the efflux of cephaloridine and cephalothin are shown in Table I l l . TABLE I The Effect of Cyanine (2.05 x 10-5 M) on the Uptake of PAH, TEA or Cephaloridine by Rabbit Renal Cortical Slices in v i t r o a
PAH Control Cyanine
19.9 • 1.5 18.9 * 2.0
Slice/Medium TEA 13.2 * 2.0 10.5 * 1.6"
Cephaloridine 6.8 * 0.8 6.6 * 0.6
* Significantly different (P < 0.05) by paired t test. a Mean * Standard Error, N = 3. TABLE I I Uptake of PAH, TEA or Cephaloridine by Renal Cortical Slices from Rabbits Pretreated (30 Minutes) with Saline or Cyanine, 4 mg/kga
PAH Control Cyanine
12.4 * 0.4 16.7 * 3.0
Slice/Medium TEA 10.2 * 0.6 5.7 * 1.0"
Cephaloridin e 4.4 * 0.6 3.9 • 0.7
* Significantly different (P < 0.05) by student's t test. a Mean * Standard Error, N = 5. TABLE I l l Efflux of 14C Cephaloridine or Cephalothin from Pre-loaded Renal Cortical Slices: Effect of Cyanine and Mepiperphenidol K (Min-1) x 103d Cephaloridine Cephalothin Control Cyanine (1.28 x 10-5 M)
11.8 * 0.5 10.3 * 0.5*
24.2 * 1.7 21.5 i 1.6
Control Mepiperphenidol (6.4 x 10-5 M)
16.3 * 1.6 12.7 * 1.6"
23.0 i 0.5 20.9 * 2.9
* Significantly different (P < 0.05) by paired t - t e s t . a Mean * Standard Error, N = 6. Both cyanine and mepiperphenidol s i g n i f i c a n t l y decreased the e f f l u x rate constant of cephaloridine while both compounds had no significant effeCt on the e f f l u x of cephalothin.
2562
Cephaloridine and Renal Cationic Transport
z
Vol. 27, No.s 25-26, 1980
\
1000-
\
-
\ Z
~
\
m
~e--t X ~ iJ.i --J
i... ,=:~
•
100-
,~O
m
PRETREATMENT (30 min)
CYANINE (4 mg/kg) o - - - . o SALINE
Z I,J,J
10
I
I
1
2
I
I
3 4 HOURS
I
I
5
6
FIG. I Renal cortical concentrations of cephaloridine in rabbits receiving cephaloridine, 100 mg/kg preceded by saline or cyanine, 4 mg/kg. Cortical concentrations at 3, 4, 5 and 6 hours were significantly greater in cyanine-pretreated animals than in controls (Student's T test, p~O.05). The results of an experiment in which cephaloridine cortical concentrations were measured at intervals after a 100 mg/kg subcutaneous dose of cephaloridine, in animals pretreated with either saline or cyanine, 4 mg/kg is presented in Figure 1. Peak concentrations were
Vol. 27, No.s 25-26, 1980
Cephaloridine and Renal Cationic Transport
2563
unaffected by cyanine pretreatment. However, cortical concentrations measured after 3 hours were significantly increased as a result of cyanine pretreatment. Discussion Previous studies from this laboratory have clearly indicated that the nephrotoxicity of cephaloridine in the rabbit can be enhanced by pretreatment with cyanine or mepiperphenidol (11). The enhancement of t o x i c i t y appears to be specific in that the toxicity of cefazolin sodium, a cephalosporin with no quarternary nitrogen group, was not affected by pretreatment with these agents. Other studies have shown that there is a close correlation between cortical concentrations of cephaloridine and resultant nephrotoxicity. Factors that alter the concentrations of cephaloridine in the renal cortex alter the t o x i c i t y ; for example, in immature rabbits in which anion transport is not developed, cephaloridine is less nephrotoxic than in adult rabbits and the cortical concentrations achieved in vivo or obtainable in vitro are significantly less in the cortex o-~ newborn rabbits ( 9 , 1 - O ' ~ . ~ t i o n a l l y , pretreatment with probenecid or other organic a n i o n s reduced cortical concentrations and subsequent nephrotoxicity (5,6,7,8). These d a t a indicate that although peak cortical concentrations are not altered by pretreatment with cyanine, the concentrations remained at a higher level when measured in vivo, and efflux measured in vitro is prolonged. These data suggest that not only peak concentratT6ns,--~ut perhaps total a r e a under the cortical concentration t i m e curve, may be an important determinant of cephaloridine nephrotoxicity. This hypothesis is also supported by the observation that the administration of cyanine after cephaloridine can also enhance cephaloridine nephrotoxicity (11). These data suggest the hypothesis that cephaloridine depends on a cationic transport out of proximal cortical tubular cells, and that this transport step then can be inhibited by the classic inhibitors of renal cation transport, such as cyanine or mepiperphenidol. Previous studies have shown that these agents can specifically inhibit an apparently active efflux of tetraethylammonium from renal cortical slices (14). Thus, although cephaloridine is dependent upon anion transport systems for entry into the proximal tubular cells, apparently cephaloridine unlike other cephalosporins does not exit readily and depends on a relatively slow, but nevertheless necessary, cationic transport step. I t is of interest to note that the efflux rates measured in these experiments for cephaloridine were significantly lower than those of cephalothin, a cephalosporin which is known to be actively secreted by the proximal tubular cells. The dependence on this cationic transport step then suggests both a mechanism for the explanation of the effect of cation transport inhibitors on cephaloridine nephrotoxicity as well as a generalized mechanism for the nephrotoxicity of cephaloridine compared to other cephalosporins which do not depend on a cation transport step for exit from proximal tubular cells. References 1.
R. M. Atkinson, J. P. Currie, B. Davis, P. A. H. Pratt, H. M. Sharpe, and E. G. Tomich, Toxicol. Appl. Pharmacol. 8, 398-406 (1966).
2564
Cephaloridine and Renal Cationic Transport
2. 3. 4. 5. 6. 7. 8. 9. i0. II. 12. 13. 14. 15. 16. 17.
Vol. 27, No.s 25-26, 1980
J . S . Welles, W. R. Gibson, P. N. Harris, R. M. Small, and R. C. Anderson, Antimicrob. A~ents Chemother. 863-869 (1965). R.D. Foord, J. Antimicrob. Chemother. Suppl. I , 119-133 (1975). G.B. Appel and H. C. Neu, New Engl. J. Med. 296, 663-721 (1977). B. M. Tune, K. Y. Wu, and R. L. Kempson, J. Pharmacol. Exp. Ther. 202, 466-471 (1977). B.M. Tune, J. Pharmacol. Exp. Ther. 181, 250-256 (1972). B. M. Tune and M. Fernholt, Amer. J. Physiol. 225, 1114-1117 (1973). K . J . Child and M. G. Dodds, B r i t . J. Pharmacol. Chemother. 30, 364-370 (1967). J. S. Wold, R. R. Joost, and N. V. Owen, J. Pharmacol. Exp. Ther. 201, 778-785 (1977). J. ~ Wold and S. A. Turnipseed, Dru9 Metab. Dispos. 6, 87-90 (1978). J. S. Wold, S. A. Turnipseed and B. L. Hawkins, Toxicol. Appl. Pharmacol. 45, 115-122 (1979). W. C. Stad-Te and B. C. Riggs, J. Biol. Chem. 154, 687-690 (1944). R. J. Cross and J. L. Taggart, Amer. J. Physiol. 161, 181-190 (1950). J. S. Wold and B. L. M i l l e r , Experentia 34, 630 (1978). J. S. Wold and S. A. Turnipseed, J. Chromatogr. 136, 170-173 (1977). R. G. D. Steel and J. H. Torrie, Principles and Procedures of Statistics. New York: McGraw-Hill (1960). A. Goldstein, B i o s t a t i s t i c s , an Introductory Text. New York: Macmillan Publishing Co., Inc. (1964).
Pergamon Press
THE EFFECTOF RENAL CATION TRANSPORTINHIBITORS ON THE IN VIVO AND IN VITRO ACCUMULATION ~LUX OF CE~RIDINE J. S. Wold, S. A. Turnipseed Toxicology Division L i l l y Research Laboratories Greenfield, Indiana, 46140
Summary I t has been shown that the nephrotoxicity of cephaloridine is enhanced by pre-treatment with the inhibitors of renal cation transport, cyanine or nw~piperphenidol. T h i s report describes experiments directed towards determining the mechanism of this effect. The nephrotoxicity of cephaloridine has been shown to be closely dependent upon renal cortical concentrations. Cyanine does not alter the uptake of cephaloridine either in vivo or in vitro. However, renal cortical concentrations c--e~-alori~Tne at later time points after the administration of the antibiotic are significantly higher in cyanine pre-treated animals. The efflux of cephaloridine from preloaded renal cortical slices is significantly slowed by the presence of cyanine or n~piperphenidol in the efflux media. It was concluded that cephaloridine depends on a relatively inactive but necessary cationic transport step for exit from proximal tubular cells and an inhibition of this transport results in increased cortical concentrations, particularly at later time points after the dose which would explain the enhanced nephrotoxicity observed after pretreatment with cation transport inhibitors. Cephaloridine is a broad-spectrum cephalosporin antibiotic that has been shown to produce dose-related nephrotoxicity in the rabbit and in other laboratory animals characterized by acute necrosis of the proximal renal tubules (1,2). The nephrotoxicity of cephaloridine has also been observed in man (3,4). The activity of the renal organic anion transport system has been shown to be an important determinant of the nephrotoxicity of cephaloridine in the rabbit. Inhibition of anion transport by probenecid or other organic anions, results in decreased cortical concentrations of cephaloridine and protects against cephaloridine nephrotoxicity (5,6,7,8). Immature rabbits accumulate less cephaloridine into the renal cortex and are relatively resistant to cephaloridine nephrotoxicity due to the incomplete development of the organic anion transport system (9,10). Although the anionic transport system is clearly important in the processes resulting in h i g h renal cortical concentrations and corresponding cortical tubular necrosis, cephaloridine is actually a zwitterion possessing a formal positive rharge on the quarternary 0024-3205/80/512559-06502.00/0 Copyright (c) 1980 Pergamon Press Ltd.
2560
Cephaloridine and Renal Cationic Transport
Vol. 27, No.s 25-26, 1980
nitrogen of the pyridinium substltuent on the beta lactam ring In addition to the anionic carboxyl group. Thus, the renal cation transport system may also influence the movement of cephaloridine into or out of the proximal tubular cells. We have previously examined the effect of the cyanine dye, cyanlne 863, an inhibitor of renal cation transport on cephalorldine nephrotoxicity. C y a n i n e administration specifically enhanced cephaloridine nephrotoxicity while the nephrotoxicity of cefazolin sodium or mercuric chloride were unaffected (11). T h i s report descrlbes an examination of the effect of cation transport inhibitors on the concentration of cephaloridine and other cephalosporins in renal cortex. We have examined the effect of cyanine on cephaloridine concentrations in vivo and on the uptake and efflux of cephaloridine in vitro. The result~ support the conclusion that cephalorldine depends on a cationic transport system for exit from proximal tubular cells, and that inhibition of cation transport results in prolonged concentrations of cephaloridine which are assumed to result in the enhanced nephrotoxicity observed. Methods
Adult female Dutch-belted rabbits were used for all experiments. haloridine (LORIDINE, Eli L i l l y and Company, Indianapolis, IN) and 4C cephaloridine and 14C cephalothin with the label in the carbonyl carbon of the thiophene-2-acetamido substituent at the 7 position were obtained from Eli L i l l y and Company, Indianapolis, IN. Cyanine dye, cyanine 863, 1-ethyl-2[(1,4-dimethyl-2-phenyl-6-pyrimidinylidine)-methyl] quinolinium chloride, referred to hereafter as cyanine, was obtained from Eastman Kodak Co., Rochester, N.Y. Mepiperphenidol was obtained from Dr. C. Sweet, Merck B Co., West Point, PA. 14C tetraethylammonium bromide (TEA) was obtained from New England Nuclear, Boston, Massachusetts. In vitro uptake and efflux studies were performed on thin slices of rena~ cortex through use of a Stadie-Riggs microtome (12). Incubations were carried out in 3 ml of the buffer of Cross and Taggart (13) with cephaloridine present at 3 x 10-4 M and PAH or TEA present at a concentration of 7.4 x 10-5 M. Incubations were carried out at 25°C under 100 oxygen for 90 minutes with a shaking rate of 100 cycles per minute. Radioactivity of TEA was determined in the trichloroacetic acid supernatant solutions as described previously (11). Efflux experiments using 14C cephaloridine or cephalothin w e r e also carried out as described previously in reports from this laboratory (14). All drug administration was carried out using the subcutaneous route of administration. Cephaloridine was measured in renal cortex in both in vitro and in vivo experiments through use of high pressure liqui--dchromatograph--y
~ep
Statistical analyses were carried out by use of student's t test (16) or the paired t test (17). Results Table I shows the accumulation of para-aminohippurate (PAH), tetraethyla~onium (TEA) and cephaloridine in tissue slices from non-treated animals in the presence or absence of cyanine. Table II presents similar data on tissue from animals pretreated with cyanine, 4 m~/kg or saline 30 minutes prior to sacrifice and preparation of cortical slices.
Vol. 27, No.s 25-26, 1980
Cephaloridine and Renal Cationic Transport
2561
Cyanine, as expected, had no effect on the uptake of PAH, and s i g n i f i c a n t l y reduced the slice:medium ratio of TEA. Cyanine, either present in the incubation medium or after pretreatment of the animals, had no effect on the renal cortical accumulation of cephaloridine. The effect of mepiperphenidol and cyanine on the efflux of cephaloridine and cephalothin are shown in Table I l l . TABLE I The Effect of Cyanine (2.05 x 10-5 M) on the Uptake of PAH, TEA or Cephaloridine by Rabbit Renal Cortical Slices in v i t r o a
PAH Control Cyanine
19.9 • 1.5 18.9 * 2.0
Slice/Medium TEA 13.2 * 2.0 10.5 * 1.6"
Cephaloridine 6.8 * 0.8 6.6 * 0.6
* Significantly different (P < 0.05) by paired t test. a Mean * Standard Error, N = 3. TABLE I I Uptake of PAH, TEA or Cephaloridine by Renal Cortical Slices from Rabbits Pretreated (30 Minutes) with Saline or Cyanine, 4 mg/kga
PAH Control Cyanine
12.4 * 0.4 16.7 * 3.0
Slice/Medium TEA 10.2 * 0.6 5.7 * 1.0"
Cephaloridin e 4.4 * 0.6 3.9 • 0.7
* Significantly different (P < 0.05) by student's t test. a Mean * Standard Error, N = 5. TABLE I l l Efflux of 14C Cephaloridine or Cephalothin from Pre-loaded Renal Cortical Slices: Effect of Cyanine and Mepiperphenidol K (Min-1) x 103d Cephaloridine Cephalothin Control Cyanine (1.28 x 10-5 M)
11.8 * 0.5 10.3 * 0.5*
24.2 * 1.7 21.5 i 1.6
Control Mepiperphenidol (6.4 x 10-5 M)
16.3 * 1.6 12.7 * 1.6"
23.0 i 0.5 20.9 * 2.9
* Significantly different (P < 0.05) by paired t - t e s t . a Mean * Standard Error, N = 6. Both cyanine and mepiperphenidol s i g n i f i c a n t l y decreased the e f f l u x rate constant of cephaloridine while both compounds had no significant effeCt on the e f f l u x of cephalothin.
2562
Cephaloridine and Renal Cationic Transport
z
Vol. 27, No.s 25-26, 1980
\
1000-
\
-
\ Z
~
\
m
~e--t X ~ iJ.i --J
i... ,=:~
•
100-
,~O
m
PRETREATMENT (30 min)
CYANINE (4 mg/kg) o - - - . o SALINE
Z I,J,J
10
I
I
1
2
I
I
3 4 HOURS
I
I
5
6
FIG. I Renal cortical concentrations of cephaloridine in rabbits receiving cephaloridine, 100 mg/kg preceded by saline or cyanine, 4 mg/kg. Cortical concentrations at 3, 4, 5 and 6 hours were significantly greater in cyanine-pretreated animals than in controls (Student's T test, p~O.05). The results of an experiment in which cephaloridine cortical concentrations were measured at intervals after a 100 mg/kg subcutaneous dose of cephaloridine, in animals pretreated with either saline or cyanine, 4 mg/kg is presented in Figure 1. Peak concentrations were
Vol. 27, No.s 25-26, 1980
Cephaloridine and Renal Cationic Transport
2563
unaffected by cyanine pretreatment. However, cortical concentrations measured after 3 hours were significantly increased as a result of cyanine pretreatment. Discussion Previous studies from this laboratory have clearly indicated that the nephrotoxicity of cephaloridine in the rabbit can be enhanced by pretreatment with cyanine or mepiperphenidol (11). The enhancement of t o x i c i t y appears to be specific in that the toxicity of cefazolin sodium, a cephalosporin with no quarternary nitrogen group, was not affected by pretreatment with these agents. Other studies have shown that there is a close correlation between cortical concentrations of cephaloridine and resultant nephrotoxicity. Factors that alter the concentrations of cephaloridine in the renal cortex alter the t o x i c i t y ; for example, in immature rabbits in which anion transport is not developed, cephaloridine is less nephrotoxic than in adult rabbits and the cortical concentrations achieved in vivo or obtainable in vitro are significantly less in the cortex o-~ newborn rabbits ( 9 , 1 - O ' ~ . ~ t i o n a l l y , pretreatment with probenecid or other organic a n i o n s reduced cortical concentrations and subsequent nephrotoxicity (5,6,7,8). These d a t a indicate that although peak cortical concentrations are not altered by pretreatment with cyanine, the concentrations remained at a higher level when measured in vivo, and efflux measured in vitro is prolonged. These data suggest that not only peak concentratT6ns,--~ut perhaps total a r e a under the cortical concentration t i m e curve, may be an important determinant of cephaloridine nephrotoxicity. This hypothesis is also supported by the observation that the administration of cyanine after cephaloridine can also enhance cephaloridine nephrotoxicity (11). These data suggest the hypothesis that cephaloridine depends on a cationic transport out of proximal cortical tubular cells, and that this transport step then can be inhibited by the classic inhibitors of renal cation transport, such as cyanine or mepiperphenidol. Previous studies have shown that these agents can specifically inhibit an apparently active efflux of tetraethylammonium from renal cortical slices (14). Thus, although cephaloridine is dependent upon anion transport systems for entry into the proximal tubular cells, apparently cephaloridine unlike other cephalosporins does not exit readily and depends on a relatively slow, but nevertheless necessary, cationic transport step. I t is of interest to note that the efflux rates measured in these experiments for cephaloridine were significantly lower than those of cephalothin, a cephalosporin which is known to be actively secreted by the proximal tubular cells. The dependence on this cationic transport step then suggests both a mechanism for the explanation of the effect of cation transport inhibitors on cephaloridine nephrotoxicity as well as a generalized mechanism for the nephrotoxicity of cephaloridine compared to other cephalosporins which do not depend on a cation transport step for exit from proximal tubular cells. References 1.
R. M. Atkinson, J. P. Currie, B. Davis, P. A. H. Pratt, H. M. Sharpe, and E. G. Tomich, Toxicol. Appl. Pharmacol. 8, 398-406 (1966).
2564
Cephaloridine and Renal Cationic Transport
2. 3. 4. 5. 6. 7. 8. 9. i0. II. 12. 13. 14. 15. 16. 17.
Vol. 27, No.s 25-26, 1980
J . S . Welles, W. R. Gibson, P. N. Harris, R. M. Small, and R. C. Anderson, Antimicrob. A~ents Chemother. 863-869 (1965). R.D. Foord, J. Antimicrob. Chemother. Suppl. I , 119-133 (1975). G.B. Appel and H. C. Neu, New Engl. J. Med. 296, 663-721 (1977). B. M. Tune, K. Y. Wu, and R. L. Kempson, J. Pharmacol. Exp. Ther. 202, 466-471 (1977). B.M. Tune, J. Pharmacol. Exp. Ther. 181, 250-256 (1972). B. M. Tune and M. Fernholt, Amer. J. Physiol. 225, 1114-1117 (1973). K . J . Child and M. G. Dodds, B r i t . J. Pharmacol. Chemother. 30, 364-370 (1967). J. S. Wold, R. R. Joost, and N. V. Owen, J. Pharmacol. Exp. Ther. 201, 778-785 (1977). J. ~ Wold and S. A. Turnipseed, Dru9 Metab. Dispos. 6, 87-90 (1978). J. S. Wold, S. A. Turnipseed and B. L. Hawkins, Toxicol. Appl. Pharmacol. 45, 115-122 (1979). W. C. Stad-Te and B. C. Riggs, J. Biol. Chem. 154, 687-690 (1944). R. J. Cross and J. L. Taggart, Amer. J. Physiol. 161, 181-190 (1950). J. S. Wold and B. L. M i l l e r , Experentia 34, 630 (1978). J. S. Wold and S. A. Turnipseed, J. Chromatogr. 136, 170-173 (1977). R. G. D. Steel and J. H. Torrie, Principles and Procedures of Statistics. New York: McGraw-Hill (1960). A. Goldstein, B i o s t a t i s t i c s , an Introductory Text. New York: Macmillan Publishing Co., Inc. (1964).