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Nephrotoxicity of low doses of tobramycin in rats: Effect of the time of administration
Life Sciences, Vol. 55, No. 3, pp. 169-17"/, 1994 Copyright © 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0024-3205/94 $6.00 + .00
Pergamon
0024-3205(94)00101-4
N E P H R O T O X I C I T Y OF LOW DOSES OF TOBRAMYCIN IN RATS: EFFECT OF THE TIME OF ADMINISTRATION
Lesheng Linl, Louis Grenierl, Guy Th6riaulO, Pierrette Gourdel, Yuji Yoshiyama3, Michel G. Bergeron l, Gaston Labrecque2, Denis Beauchampl 1Laboratoire et Service d'Infectiologie, Centre de Recherche du Centre Hospitalier de l'Universit6 Laval, and D6partement de Microbiologie, Facult6 de M6decine, Universit6 Laval, Ste-Foy, Qu6bec, Canada, G 1V 4G2 2E~cole de Pharmacie, Universit6 Lavai, and D6partement de Pharmacie, Centre Hospitalier de l'Universit6 Laval, Ste-Foy, Qu6bec, Canada, G1K 71:'4 3School of Pharmaceutical Sciences, Kitasato University, Tokyo 108, Japan (Received in final f o r m May 2, 1994)
Summary The circadian and the circannual variations of the nephrotoxicity of tobramycin were studied in female Sprague-Dawley rats. Animals were maintained on a lightdark period of 14/10 hrs (light on: 06h00 to 20h00). They were injected once daily for 4 and 10 days with saline or tobramycin at a dose of 40 mg/kg/day i.p, at either 08h00, 14h00, 20h00 and 02h00, in April 1991, July 91, October 91, January 92. In April 91, tobramycin injected at 14h00 during 10 days induced a significant increase of [3H]-thymidine incorporation into DNA of renal cortex as compared to other groups (p < 0.01): toxicity was highest at 14h00 and lowest at 02h00. No temporal change was observed in the renal cortical accumulation of tobramycin, and in serum creatinine after the 4 or 10 days of treatment. In experiments done in April, July and October 1991 and in January 1992, no circannual variation was found in tobramycin cortical levels but peaks of toxicity were observed at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. There was no linear correlation between the toxicity and the tobramycin accumulation in the renal cortex (r = 0.21). The data suggest that the circadian changes in tobramycin toxicity are due to temporal changes in the susceptibility of renal cells to tobramycin. Key Words: tobramycin, nephrotoxicity, chronotoxicity
Over the last 30 years, aminoglycosides have been used either alone or in combination with other antimicrobial agents for treatment of Gram (-) bacillary infections. In combination with vancomycin or 13-1actam antibiotics, aminoglycosides are agents of choice for many types of infections caused by Streptococci, Staphylococci and Pseudomonas (1, 2). Unfortunately, the use of aminoglycosides is often associated with dose-related renal toxicity and auditory damage. In patients (3, 4, 5) as in experimental animals (5, 6), renal toxicity of aminoglycosides has been associated with many risk factors. Different approaches such as the concomitant administration of poly-L-aspartic acid and daptomycin in animals (7, 8, 9, 10, 11) have been recently identified to reduce significantly the renal toxicity of aminoglycosides. One approach that needs to continue to be explored and which has a high clinical relevance is the once-daily Corresponding author: Denis Beauchamp Ph.D., Laboratoire et Service d'Infectiologie, Centre de Recherche du CHUL, 2705 Boul. Laurier, Ste-Foy, P. QuEbec, Canada, G1V 4G2.
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administration of aminoglycosides. Bennett et al. (12) were the first to demonstrate the lower toxicity of once-daily regimen as compared to more frequent dosing in experimental animals. Once-daily dosing has been shown to be safe and effective in the treatment of experimental E s c h e r i c h i a coli (13) and streptococcal (14) endocarditis. Recent studies reported similar efficacy (15, 16) and a lower toxicity (15) of once-daily dosing than conventional therapy in patients. Another factor which may be of clinical importance and that has been neglected in previous experimental and clinical studies is the circadian toxicity of aminoglycosides. Nakano and Ogawa (17) were the first to report a temporal change in the LDs0 of aminoglycosides. In fact, they noted that gentamicin kills more mice when injected in the middle of the light period of the day than when the same dose was injected during the midnight. Several other investigators have also evaluated the chrononephrotoxicity of aminoglycosides (18, 19, 20, 21, 22, 23). The aim of this study was to investigate the circadian and circannual variations in the nephrotoxicity of low doses of tobramycin by using specific and sensitive parameters of nephrotoxicity in rats. Materials and methods
Animals and treatments. Female Sprague-Dawley rats weighing between 180-260 g were used. They had free access to food and water throughout the experiment. Animals were maintained on a 14 h light and 10 h dark period cycle (light on: 06h00 to 20h00) for 2 weeks before and during all experiments. In April 91, saline (NaCI, 0.9%, control animals) or tobramycin (40 mg/kg/day) were injected i.p. to different groups of rats (n=6 rats/group) at either 08h00, 14h00, 20h00 and 02h00. This experiment was repeated in July 91, October 91, and January 92. Animals were killed by decapitation 16-20 hours after the last injection. One hour before sacrifice, each animal received an i.p. injection of [3H]-thymidine (200/aCi). At the time of sacrifice, the blood was collected, and the serum was immediately frozen. Both kidneys were rapidly removed and bisected. The cortex of one half of the left kidney was dissected and quickly frozen in dry ice for further determination of the [3H]-thymidine/DNA ratio. The cortex of the other half was also dissected and quickly frozen for tobramycin assays. The cortex of both parts of the right kidney was also dissected for further biochemical analysis.
Tobramycin assays. The renal cortical accumulation of tobramycin was measured by a fluorescence polarized immunoassay (TDX system, Abbott Laboratories, North Chicago, Ill.), as reported previously (30). Briefly, samples of kidney cortex were homogenized in distilled water with a Tissue-Tearor RTM (Biospec Products, Bartlesville, OK). The homogenates were sonicated with a sonicator (model W-375, Bionetics Ltd., Montr6al, Qu6bec, Canada) and diluted in the TDX buffer (Abbott Laboratories, North Chicago, Ill.) to obtain concentrations between 2 and 8/ag/ml of tobramycin. The interday coefficients of variation were 3.6% at 1 ,ug/ml and 3.4 % at 8/ag/ml. Biochemical analysis. The measurement of DNA specific radioactivity was performed as described by Laurent et al. (24) on purified DNA obtained from the cortical tissue of the left kidneys. The radioactivity ([3H]-thymidine) was counted in a liquid scintillation counter (LS 6000TA, Beckman, Instruments Inc., Fullerton, CA.) and DNA concentration in each sample was measured using a spectrophotometer (Easy Reader, EAR-400, SLT-Labinstruments, Austria). Creatinine levels in serum were determined by an urea nitrogen-creatinine analyzer (ABA-100, Abbott). Statistics. All statistical analysis were performed on StatViewTM SE + Graphics ©1988 (Abacus Concepts Inc., Berkeley, CA). Difference between groups was performed by analysis of variance (Anova). If F-test indicated a difference within groups (p<0.05), group comparisons were performed using the Fisher's PLSD test and t><0.05 was considered significant.
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Materials. Rats were purchased from Charles River Inc. (Montr6al, Qu6bec, Canada). Tobramycin was a gift from Eli Lilly Canada Inc. (Scarborough,Ontario, Canada). [methyl-3H]thymidine (49 Ci/mmol) came from Amersham Canada Ltd. (Oakville, Ontario, Canada). DNA (from salmon testis type Ili) came from Sigma Chemical Co. (St. Louis, Mo.). Other reagents were of analytical grade and were purchased from Fisher Scientific Ltd. (Qu6bec, Qu6bec, Canada) and Sigma. Results
Circadian variation of the nephrotoxieity of tobramycin observed in April 1991, Figure 1 shows the increase of [3H]-thymidine incorporation into DNA of renal cortex measured after 4 and 10 days of treatment with tobramycin given at either 08h00, 14h00, 20h00 and 02h00. Results are expressed in percent changes from the respective time-matched controls. After 4 days of treatment, no significant difference was observed between groups. After 10 days of treatment, the cellular regeneration was significantly higher in animals treated at 14h00 than at 20h00 (p < 0.01) and 02h00 (p < 0.01). This figure indicates also that the cellular regeneration was lowest when rats received tobramycin at 02h00 and it was highest after the 14h00 dose. In fact, the cellular regeneration was always larger in animals treated with tobramycin at the different hours of day than in their respective matched control groups, except for the animals treated at 02h00. Serum creatinine levels were monitored to evaluate renal function. No change was found in serum creatinine levels after 4 day of treatment and Figure 2 shows that similar data was obtained on Day 10. Figure 3 shows the accumulation of tobramycin in the renal cortex but no significant difference was found between the different groups of rats receiving saline or tobramycin even after l0 days of treatment. Cireannual variations in the nephrotoxicity of tobramyein. The circadian variation in the nephrotoxicity of the tobramycin was studied also at different months of the year. In experiments carried out in April, July and October 1991 and in January 1992, 24-hr variations were found in the thymidine incorporation into renal cells of rats treated for 10 days with tobramycin (40 mg/kg). The data obtained throughout the year were similar to those found in April 1991. Nephrotoxicity was never found when tobramycin was injected at 02h00 as the thymidine incorporation into DNA of treated rats and matched controls was not significantly different (p > 0.05) from one another. However, significant nephrotoxicity was always found when the aminoglycoside was injected at 08h00 (p < 0.05) and at 14h00 (p < 0.0001). The upper graph of Figure 4 shows that no circannual variation could be detected in peak toxicity as the highest thymidine incorporation was not significantly different (p > 0.05) throughout the year. This figure indicates also that the time of appearance of peak values was found at 14h00 throughout the year, except in October 1991 where peak thymidine incorporation was found at 08h00. Circannual changes in peak cortical accumulation of tobramycin. The accumulation of tobramycin in renal cortical cells was also studied at 4 months of the year. Figure 4 (lower graph) illustrates that peak accumulation of the aminoglycoside in the ceils of renal cortex did not vary significantly (p > 0.05) throughout the year but the time of occurrence of peak accumulation was found at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. Correlation between cortical tobramycin levels and cellular regeneration. The correlation between the [3H]-thymidine incorporation into DNA and the accumulation of tobramycin in the renal cortex were determined. The low coefficient of correlation, (r =0.21, p = 0.373) is suggesting that there was no evidence of a direct relationship between the cellular regeneration and the cortical accumulation of tobramycin. Discussion The present study shows a circadian variation in the nephrotoxicity of tobramycin, In fact, the [3H]-thymidine incorporation into DNA was maximal in the middle of the rest period of the rats and minimal during the middle of the activity period of the animals. These changes were observed in the presence of similar cortical accumulation of tobramycin in the renal cortex. Normal creatinine levels in serum measured in all tobramycin treated-groups indicates
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Fig, 1 [3H]-thymidine incorporation into DNA in the renal cortex of rats. Tobramycin (40 mg/kg/day) was given i.p. once-daily for 4 and 10 days at either 08h00, 14h00, 20h00, and 02h00. The data are presented as mean percent changes + SD of drug-treated groups over the matched controls at each time points. The asterisks (*: p < 0.05; **: p < 0.01) indicate the statistical differences between the groups under the extremity of the line. Open boxes: light period; Close boxes: dark period. that the dose used (40 mg/kg/day, i.p. for 10 days) did not induce a reduction of the glomerular filtration rate. The chronopharmacology and chronotoxicity of aminoglycosides have already been described by other investigators using different parameters of toxicity such as the LDs0, urinary enzyme excretion and histopathology. Nakano and Ogawa (17) reported that gentamicin killed more mice when the same dose of drug was injected in the middle of the rest period (13h00) than in the middle of activity (01h00). On the other hand, Pariat et al. (18) showed that gentamicin, dibekacin and netilmicin killed less mice when administered at the beginning of the dark period (20h00) while they were more toxic when injected at the beginning of the rest period (08h00). Another study showed that the lethality in mice was maximal at 02h00 and minimal at 14h00 in November/December but was maximal at 14h00 and minimal at 02h00 in March/April, suggesting a circannual variation in the toxicity of amikacin (25). Dorian and Cambar (26) reported that the highest urinary excretion of ~t-glutamyltransferase occurred at 20h00 and the lowest excretion was found following a single injection of amikacin given at 14h00. In other studies, Pariat et al. (19) demonstrated that the increase in the urinary excretion of renal tubular
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Fig. 3 Tobramycin levels in the renal cortex of rats injected i.p. with tobramycin during 4 and 10 days in April 1991. Tobramycin (40 mg/kg/day) was given once-daily at either 08h00, 14h00, 20h00, and 02h00. Data are expressed as mean values (in/,g/ml tissue) + S.D. obtained in groups of 6 rats. Open boxes, light period; Close boxes, dark period. brush border enzymes alanine aminopeptidase and y-glutamyltransferase increased significantly after a single injection of gentamicin given at 20h00, but no increase was observed when the drug was injected at 08h00. By contrast, the enzyme excretion following a single injection of gentamicin was maximal at 14h00 and minimal when the drug was injected at 20h00 (20). Seasonal differences were also reported (27). Dorian et al. (28) used urinary enzyme excretion in rats and they showed that the maximal toxicity of a 7 days treatment with 400 mg/kg amikacin daily doses occurred when the drug was given at 14h00. More recently, Yoshiyama e t al. (23) reported a severe renal toxicity in rats following midlight (13h00) administration of gentamicin compared with the middark (01h00). A similar significant circadian rhythm was shown for plasma and renal gentamicin concentrations after drug administration (23). A circadian variation in the nephrotoxicity of the combination gentamicin-vancomycin was also reported (21). Circadian variations in the pharmacokinetics of aminoglycoside has already been demonstrated in human. In fact, Nakano et al. (22) observed a significant circadian rhythm for
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Tobramycin Chrononephrotoxicity
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Fig. 4 Determination of the peak values of the [3H]-thymidine incorporation into DNA (upper graph) and the cortical accumulation of tobramycin (lower graph) at 4 months of the year. Groups of 6 rats were treated at either 08h00, 14h00, 20h00, and 02h00 during 10 days in April 1991, July 1991, October 91 and January 92. Values of the [31-1]thymidine incorporation into DNA are expressed as the mean + SD percentage of the matched control values. gentamicin kinetics with the lowest clearance, the longer half-life and the larger AUC measured at midnight. Circadian variation in the serum concentrations of netilmicin was also found with a maximum level at 05h00 and trough level at 09h00 (29). In the present study, the ratio of [3H]-thymidine incorporation into DNA shows a significant circadian variation. In April 91, July 91, and January 92, the highest toxicity was measured when the drug was injected at 14hO0, and the lowest toxicity was observed at 02h00. In October 1991, the highest toxicity appeared most likely at the beginning of the light period (08h00) instead of the middle of the light period (14h00). Our results are thus not consistent with the existence of circannual variations of the nephrotoxicity of tobramycin as suggested by Pariat et al., (18, 27). Our data published recently (30) showed that the cellular regeneration was a sensitive parameter for tobramycin-induced circadian toxicity as similar results were obtained when other parameters such as the urinary excretion of renal enzymes were used (30). Thus, we can conclude that the lower [3H]-thymidine incorporation into DNA observed in rats treated at 02h00 is not due to a circadian variation in the cellular repair mechanism. Our data are in agreement to those observed in a gentamicin-induced mortality study in mice following a single injection (18) and to those found when rats treated for 7 or 8 consecutive days with amikacin (28) and gentamicin (23). However, different results were noted when the renal toxicity of single-dose aminoglycoside regimen was studied when parameters of toxicity
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such as the lethality (17) and the urinary enzyme excretion were used (19, 20, 26). These discrepancies might be due to the fact that these studies were done with different drugs, doses, frequencies, and parameters of toxicity. Only few investigators have looked at circadian variations in the intracortical accumulation of aminoglycoside as a possible mechanism of their circadian nephrotoxicity (20, 23). A good correlation was reported between the circadian toxicity and the cortical accumulation of gentamicin following a single (20) or multiple injections (23). Although a direct relationship between the renal accumulation of aminoglycosides and their toxicity has not always been observed, one cannot exclude the possibility of significant changes in the renal uptake of these drugs as a function of time of the day. In the present study, no significant change was observed throughout the day or the year in the cortical accumulation of tobramycin after 4 and 10 days of treatment. Significant changes in the peak serum levels of tobramycin, clearance of the drug, serum half-live, or AUC in serum for the different time of injection might have occurred without inducing significant detectable difference in the overall tissular accumulation of tobramycin following 4 and 10 days of treatment. Figure 5 shows a low correlation between the toxicity and the intracortical accumulation of tobramycin. Different mechanisms were suggested to explain the circadian and the circannual variations of the nephrotoxicity of aminoglycosides observed in experimental animals. In acute mortality studies, animals died most likely from neuromuscular blockage rather than from acute renal failure (17, 18, 25) because high doses of aminosides were injected to rodents. Other mechanisms are the circadian rhythms of the urinary excretion of water, electrolytes and of the renal perfusion (20, 25, 27), the circadian variations in the membrane structure and fluidity and in the number and size of autophagic vacuoles in the cytoplasm of tubular cells (20), the circadian rhythm in the pharmacokinetics of aminoglycoside (22, 23) and a circadian rhythm in the urinary volume in rats (27). Other studies done in our laboratory shows a significant lower AUC in serum and higher serum clearance of tobramycin when the drug is injected at 02h00 than at 14h00 (30). In human, temporal variations in the kinetics of the drug elimination seem to correlate well with the toxicity (22, 29). Finally, a recent study indicate that peak and trough of the body temperature may serve as markers of the resistance and susceptibility to gentamicininduced ototoxicity in rats (31). The clinical relevance of the chronopharmacology and chronotoxicity of aminoglycosides is of importance in view of the recent investigations on the efficacy and nephrotoxicity of prolonged dosage intervals of aminoglycosides given as the same total daily doses. In experimental animals, it was clearly demonstrated that once daily administration of aminoglycosides was less toxic (12) but still effective in the treatment of different experimental models of infectious diseases (13, 14, 32). Recent clinical studies also reported that treatment of a variety of infections with a single daily dose of an aminoglycoside alone or combined with a 13-1actam antibiotic is safe and effective (15, 16, 33, 34). Moreover, the occurrence of renal toxicity was delayed when patients suffering of serious bacterial infections were treated with the once-daily regimen of netilmicin in comparison with the multiple daily injections (15). Urinary excretion of phospholipids was also lower in patients with urinary tract infections treated with a single daily regimen of netilmicin as compared to those receiving three daily injections (34). Based on the results of the present study, the mechanism of the chronotoxicity of tobramycin is still obscure. Factors such as temporal changes of the susceptibility of renal cells, circadian variations of endogenous hormones, and changes in the pharmacokinetics of tobramycin might as a whole or in part be responsible for the chrononephrotoxicity of tobramycin observed in the present study. Further research is needed to identify completely the mechanisms of aminoside chrononephrotoxicity. Acknowledgments This work was supported by The Kidney Foundation of Canada. Denis Beauchamp is recipient of a Fonds de la Recherche en Sant6 du QuEbec/Eli Lilly Scholarship.
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Pergamon
0024-3205(94)00101-4
N E P H R O T O X I C I T Y OF LOW DOSES OF TOBRAMYCIN IN RATS: EFFECT OF THE TIME OF ADMINISTRATION
Lesheng Linl, Louis Grenierl, Guy Th6riaulO, Pierrette Gourdel, Yuji Yoshiyama3, Michel G. Bergeron l, Gaston Labrecque2, Denis Beauchampl 1Laboratoire et Service d'Infectiologie, Centre de Recherche du Centre Hospitalier de l'Universit6 Laval, and D6partement de Microbiologie, Facult6 de M6decine, Universit6 Laval, Ste-Foy, Qu6bec, Canada, G 1V 4G2 2E~cole de Pharmacie, Universit6 Lavai, and D6partement de Pharmacie, Centre Hospitalier de l'Universit6 Laval, Ste-Foy, Qu6bec, Canada, G1K 71:'4 3School of Pharmaceutical Sciences, Kitasato University, Tokyo 108, Japan (Received in final f o r m May 2, 1994)
Summary The circadian and the circannual variations of the nephrotoxicity of tobramycin were studied in female Sprague-Dawley rats. Animals were maintained on a lightdark period of 14/10 hrs (light on: 06h00 to 20h00). They were injected once daily for 4 and 10 days with saline or tobramycin at a dose of 40 mg/kg/day i.p, at either 08h00, 14h00, 20h00 and 02h00, in April 1991, July 91, October 91, January 92. In April 91, tobramycin injected at 14h00 during 10 days induced a significant increase of [3H]-thymidine incorporation into DNA of renal cortex as compared to other groups (p < 0.01): toxicity was highest at 14h00 and lowest at 02h00. No temporal change was observed in the renal cortical accumulation of tobramycin, and in serum creatinine after the 4 or 10 days of treatment. In experiments done in April, July and October 1991 and in January 1992, no circannual variation was found in tobramycin cortical levels but peaks of toxicity were observed at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. There was no linear correlation between the toxicity and the tobramycin accumulation in the renal cortex (r = 0.21). The data suggest that the circadian changes in tobramycin toxicity are due to temporal changes in the susceptibility of renal cells to tobramycin. Key Words: tobramycin, nephrotoxicity, chronotoxicity
Over the last 30 years, aminoglycosides have been used either alone or in combination with other antimicrobial agents for treatment of Gram (-) bacillary infections. In combination with vancomycin or 13-1actam antibiotics, aminoglycosides are agents of choice for many types of infections caused by Streptococci, Staphylococci and Pseudomonas (1, 2). Unfortunately, the use of aminoglycosides is often associated with dose-related renal toxicity and auditory damage. In patients (3, 4, 5) as in experimental animals (5, 6), renal toxicity of aminoglycosides has been associated with many risk factors. Different approaches such as the concomitant administration of poly-L-aspartic acid and daptomycin in animals (7, 8, 9, 10, 11) have been recently identified to reduce significantly the renal toxicity of aminoglycosides. One approach that needs to continue to be explored and which has a high clinical relevance is the once-daily Corresponding author: Denis Beauchamp Ph.D., Laboratoire et Service d'Infectiologie, Centre de Recherche du CHUL, 2705 Boul. Laurier, Ste-Foy, P. QuEbec, Canada, G1V 4G2.
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administration of aminoglycosides. Bennett et al. (12) were the first to demonstrate the lower toxicity of once-daily regimen as compared to more frequent dosing in experimental animals. Once-daily dosing has been shown to be safe and effective in the treatment of experimental E s c h e r i c h i a coli (13) and streptococcal (14) endocarditis. Recent studies reported similar efficacy (15, 16) and a lower toxicity (15) of once-daily dosing than conventional therapy in patients. Another factor which may be of clinical importance and that has been neglected in previous experimental and clinical studies is the circadian toxicity of aminoglycosides. Nakano and Ogawa (17) were the first to report a temporal change in the LDs0 of aminoglycosides. In fact, they noted that gentamicin kills more mice when injected in the middle of the light period of the day than when the same dose was injected during the midnight. Several other investigators have also evaluated the chrononephrotoxicity of aminoglycosides (18, 19, 20, 21, 22, 23). The aim of this study was to investigate the circadian and circannual variations in the nephrotoxicity of low doses of tobramycin by using specific and sensitive parameters of nephrotoxicity in rats. Materials and methods
Animals and treatments. Female Sprague-Dawley rats weighing between 180-260 g were used. They had free access to food and water throughout the experiment. Animals were maintained on a 14 h light and 10 h dark period cycle (light on: 06h00 to 20h00) for 2 weeks before and during all experiments. In April 91, saline (NaCI, 0.9%, control animals) or tobramycin (40 mg/kg/day) were injected i.p. to different groups of rats (n=6 rats/group) at either 08h00, 14h00, 20h00 and 02h00. This experiment was repeated in July 91, October 91, and January 92. Animals were killed by decapitation 16-20 hours after the last injection. One hour before sacrifice, each animal received an i.p. injection of [3H]-thymidine (200/aCi). At the time of sacrifice, the blood was collected, and the serum was immediately frozen. Both kidneys were rapidly removed and bisected. The cortex of one half of the left kidney was dissected and quickly frozen in dry ice for further determination of the [3H]-thymidine/DNA ratio. The cortex of the other half was also dissected and quickly frozen for tobramycin assays. The cortex of both parts of the right kidney was also dissected for further biochemical analysis.
Tobramycin assays. The renal cortical accumulation of tobramycin was measured by a fluorescence polarized immunoassay (TDX system, Abbott Laboratories, North Chicago, Ill.), as reported previously (30). Briefly, samples of kidney cortex were homogenized in distilled water with a Tissue-Tearor RTM (Biospec Products, Bartlesville, OK). The homogenates were sonicated with a sonicator (model W-375, Bionetics Ltd., Montr6al, Qu6bec, Canada) and diluted in the TDX buffer (Abbott Laboratories, North Chicago, Ill.) to obtain concentrations between 2 and 8/ag/ml of tobramycin. The interday coefficients of variation were 3.6% at 1 ,ug/ml and 3.4 % at 8/ag/ml. Biochemical analysis. The measurement of DNA specific radioactivity was performed as described by Laurent et al. (24) on purified DNA obtained from the cortical tissue of the left kidneys. The radioactivity ([3H]-thymidine) was counted in a liquid scintillation counter (LS 6000TA, Beckman, Instruments Inc., Fullerton, CA.) and DNA concentration in each sample was measured using a spectrophotometer (Easy Reader, EAR-400, SLT-Labinstruments, Austria). Creatinine levels in serum were determined by an urea nitrogen-creatinine analyzer (ABA-100, Abbott). Statistics. All statistical analysis were performed on StatViewTM SE + Graphics ©1988 (Abacus Concepts Inc., Berkeley, CA). Difference between groups was performed by analysis of variance (Anova). If F-test indicated a difference within groups (p<0.05), group comparisons were performed using the Fisher's PLSD test and t><0.05 was considered significant.
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Materials. Rats were purchased from Charles River Inc. (Montr6al, Qu6bec, Canada). Tobramycin was a gift from Eli Lilly Canada Inc. (Scarborough,Ontario, Canada). [methyl-3H]thymidine (49 Ci/mmol) came from Amersham Canada Ltd. (Oakville, Ontario, Canada). DNA (from salmon testis type Ili) came from Sigma Chemical Co. (St. Louis, Mo.). Other reagents were of analytical grade and were purchased from Fisher Scientific Ltd. (Qu6bec, Qu6bec, Canada) and Sigma. Results
Circadian variation of the nephrotoxieity of tobramycin observed in April 1991, Figure 1 shows the increase of [3H]-thymidine incorporation into DNA of renal cortex measured after 4 and 10 days of treatment with tobramycin given at either 08h00, 14h00, 20h00 and 02h00. Results are expressed in percent changes from the respective time-matched controls. After 4 days of treatment, no significant difference was observed between groups. After 10 days of treatment, the cellular regeneration was significantly higher in animals treated at 14h00 than at 20h00 (p < 0.01) and 02h00 (p < 0.01). This figure indicates also that the cellular regeneration was lowest when rats received tobramycin at 02h00 and it was highest after the 14h00 dose. In fact, the cellular regeneration was always larger in animals treated with tobramycin at the different hours of day than in their respective matched control groups, except for the animals treated at 02h00. Serum creatinine levels were monitored to evaluate renal function. No change was found in serum creatinine levels after 4 day of treatment and Figure 2 shows that similar data was obtained on Day 10. Figure 3 shows the accumulation of tobramycin in the renal cortex but no significant difference was found between the different groups of rats receiving saline or tobramycin even after l0 days of treatment. Cireannual variations in the nephrotoxicity of tobramyein. The circadian variation in the nephrotoxicity of the tobramycin was studied also at different months of the year. In experiments carried out in April, July and October 1991 and in January 1992, 24-hr variations were found in the thymidine incorporation into renal cells of rats treated for 10 days with tobramycin (40 mg/kg). The data obtained throughout the year were similar to those found in April 1991. Nephrotoxicity was never found when tobramycin was injected at 02h00 as the thymidine incorporation into DNA of treated rats and matched controls was not significantly different (p > 0.05) from one another. However, significant nephrotoxicity was always found when the aminoglycoside was injected at 08h00 (p < 0.05) and at 14h00 (p < 0.0001). The upper graph of Figure 4 shows that no circannual variation could be detected in peak toxicity as the highest thymidine incorporation was not significantly different (p > 0.05) throughout the year. This figure indicates also that the time of appearance of peak values was found at 14h00 throughout the year, except in October 1991 where peak thymidine incorporation was found at 08h00. Circannual changes in peak cortical accumulation of tobramycin. The accumulation of tobramycin in renal cortical cells was also studied at 4 months of the year. Figure 4 (lower graph) illustrates that peak accumulation of the aminoglycoside in the ceils of renal cortex did not vary significantly (p > 0.05) throughout the year but the time of occurrence of peak accumulation was found at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. Correlation between cortical tobramycin levels and cellular regeneration. The correlation between the [3H]-thymidine incorporation into DNA and the accumulation of tobramycin in the renal cortex were determined. The low coefficient of correlation, (r =0.21, p = 0.373) is suggesting that there was no evidence of a direct relationship between the cellular regeneration and the cortical accumulation of tobramycin. Discussion The present study shows a circadian variation in the nephrotoxicity of tobramycin, In fact, the [3H]-thymidine incorporation into DNA was maximal in the middle of the rest period of the rats and minimal during the middle of the activity period of the animals. These changes were observed in the presence of similar cortical accumulation of tobramycin in the renal cortex. Normal creatinine levels in serum measured in all tobramycin treated-groups indicates
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Fig. 3 Tobramycin levels in the renal cortex of rats injected i.p. with tobramycin during 4 and 10 days in April 1991. Tobramycin (40 mg/kg/day) was given once-daily at either 08h00, 14h00, 20h00, and 02h00. Data are expressed as mean values (in/,g/ml tissue) + S.D. obtained in groups of 6 rats. Open boxes, light period; Close boxes, dark period. brush border enzymes alanine aminopeptidase and y-glutamyltransferase increased significantly after a single injection of gentamicin given at 20h00, but no increase was observed when the drug was injected at 08h00. By contrast, the enzyme excretion following a single injection of gentamicin was maximal at 14h00 and minimal when the drug was injected at 20h00 (20). Seasonal differences were also reported (27). Dorian et al. (28) used urinary enzyme excretion in rats and they showed that the maximal toxicity of a 7 days treatment with 400 mg/kg amikacin daily doses occurred when the drug was given at 14h00. More recently, Yoshiyama e t al. (23) reported a severe renal toxicity in rats following midlight (13h00) administration of gentamicin compared with the middark (01h00). A similar significant circadian rhythm was shown for plasma and renal gentamicin concentrations after drug administration (23). A circadian variation in the nephrotoxicity of the combination gentamicin-vancomycin was also reported (21). Circadian variations in the pharmacokinetics of aminoglycoside has already been demonstrated in human. In fact, Nakano et al. (22) observed a significant circadian rhythm for
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such as the lethality (17) and the urinary enzyme excretion were used (19, 20, 26). These discrepancies might be due to the fact that these studies were done with different drugs, doses, frequencies, and parameters of toxicity. Only few investigators have looked at circadian variations in the intracortical accumulation of aminoglycoside as a possible mechanism of their circadian nephrotoxicity (20, 23). A good correlation was reported between the circadian toxicity and the cortical accumulation of gentamicin following a single (20) or multiple injections (23). Although a direct relationship between the renal accumulation of aminoglycosides and their toxicity has not always been observed, one cannot exclude the possibility of significant changes in the renal uptake of these drugs as a function of time of the day. In the present study, no significant change was observed throughout the day or the year in the cortical accumulation of tobramycin after 4 and 10 days of treatment. Significant changes in the peak serum levels of tobramycin, clearance of the drug, serum half-live, or AUC in serum for the different time of injection might have occurred without inducing significant detectable difference in the overall tissular accumulation of tobramycin following 4 and 10 days of treatment. Figure 5 shows a low correlation between the toxicity and the intracortical accumulation of tobramycin. Different mechanisms were suggested to explain the circadian and the circannual variations of the nephrotoxicity of aminoglycosides observed in experimental animals. In acute mortality studies, animals died most likely from neuromuscular blockage rather than from acute renal failure (17, 18, 25) because high doses of aminosides were injected to rodents. Other mechanisms are the circadian rhythms of the urinary excretion of water, electrolytes and of the renal perfusion (20, 25, 27), the circadian variations in the membrane structure and fluidity and in the number and size of autophagic vacuoles in the cytoplasm of tubular cells (20), the circadian rhythm in the pharmacokinetics of aminoglycoside (22, 23) and a circadian rhythm in the urinary volume in rats (27). Other studies done in our laboratory shows a significant lower AUC in serum and higher serum clearance of tobramycin when the drug is injected at 02h00 than at 14h00 (30). In human, temporal variations in the kinetics of the drug elimination seem to correlate well with the toxicity (22, 29). Finally, a recent study indicate that peak and trough of the body temperature may serve as markers of the resistance and susceptibility to gentamicininduced ototoxicity in rats (31). The clinical relevance of the chronopharmacology and chronotoxicity of aminoglycosides is of importance in view of the recent investigations on the efficacy and nephrotoxicity of prolonged dosage intervals of aminoglycosides given as the same total daily doses. In experimental animals, it was clearly demonstrated that once daily administration of aminoglycosides was less toxic (12) but still effective in the treatment of different experimental models of infectious diseases (13, 14, 32). Recent clinical studies also reported that treatment of a variety of infections with a single daily dose of an aminoglycoside alone or combined with a 13-1actam antibiotic is safe and effective (15, 16, 33, 34). Moreover, the occurrence of renal toxicity was delayed when patients suffering of serious bacterial infections were treated with the once-daily regimen of netilmicin in comparison with the multiple daily injections (15). Urinary excretion of phospholipids was also lower in patients with urinary tract infections treated with a single daily regimen of netilmicin as compared to those receiving three daily injections (34). Based on the results of the present study, the mechanism of the chronotoxicity of tobramycin is still obscure. Factors such as temporal changes of the susceptibility of renal cells, circadian variations of endogenous hormones, and changes in the pharmacokinetics of tobramycin might as a whole or in part be responsible for the chrononephrotoxicity of tobramycin observed in the present study. Further research is needed to identify completely the mechanisms of aminoside chrononephrotoxicity. Acknowledgments This work was supported by The Kidney Foundation of Canada. Denis Beauchamp is recipient of a Fonds de la Recherche en Sant6 du QuEbec/Eli Lilly Scholarship.
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