The two-compartment tissue accumulation pharmacokinetics of tobramycin and netilmicin were compared in 11 normal volunteers by using a crossover design.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1987,
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Vol. 31, No. 4
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0066-4804/87/040605-05$02.00/0 Copyright © 1987, American Society for Microbiology
Single-Dose Accumulation Pharmacokinetics of Tobramycin and Netilmicin in Normal Volunteers NANCY E. WINSLADE, MARTIN H. ADELMAN, EVAN J. EVANS, AND JEROME J. SCHENTAG* Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York 14260, and The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospitals, Buffalo, New York 14209 Received 30 October 1986/Accepted 21 January 1987
The two-compartment tissue accumulation pharmacokinetics of tobramycin and netilmicin were compared in 11 normal volunteers by using a crossover design. After each 1.0-mg/kg (body weight) dose, serum was collected for 96 h, and complete 24-h urine collections were obtained for a total of 30 days. Two months of washout were required before crossover. Concentrations in serum and urine were measured by radioimmunoassay, and concentrations in serum and urinary excretion rates were simultaneously fitted to a twocompartment pharmacokinetic model. Netilmicin exhibited significantly lower total body clearance (48 versus 90 ml/min) and longer terminal elimination half-life (161 versus 96 h) than tobramycin. As a result of these pharmacokinetic differences, the predicted tissue accumulation of netilmicin at steady state was significantly higher than that of tobramycin (P < 0.05). Relative rates of aminoglycoside nephrotoxicity probably depend on both the differential tissue uptake (accumulation) and the concentration of the aminoglycoside which produces intracellular toxicity. Because the steady-state tissue accumulation of netilmicin is nearly 2.5 times greater than that of tobramycin, its potency in the production of intracellular toxicity needs to be that much less for the two agents to produce the same incidence of clinical nephrotoxicity.
tion potential than even gentamicin (4, 10, 18, 20), this agent causes less nephrotoxicity in rats (4, 14, 15, 18, 20). Less nephrotoxicity in the face of greater tissue accumulation raises the hypothesis that not only accumulation but also the potency of the drug against one or more intracellular receptors is important in the pathogenesis of nephrotoxicity (4). The normal volunteer, single-dose model for tissue accumulation pharmacokinetics has the advantage of relative safety and obviates the need for large numbers of subjects in the presence of the large interindividual variations in aminoglycoside disposition. In this study, the normal volunteer model was used to compare the human tissue accumulation profiles of netilmicin and tobramycin and to determine whether the same differences occurred as found in rats.
Although aminoglycosides are often drugs of choice for many gram-negative infections, their use has been hampered by concerns of nephrotoxicity. For several reasons, however, it has been difficult to clinically determine the true, relative incidence of this side effect. Because nephrotoxicity occurs in a low percentage of treated patients, clinical trials must enter large numbers of patients to show statistical differences between aminoglycosides. Confounding variables which affect the incidence of nephrotoxicity, including concurrent diseases, medications, and age (23), must be considered and balanced between populations. Finally, clinical parameters, such as elevated serum creatinine, may not be specific for aminoglycoside-associated toxicity but may also reflect renal injury due to a variety of other causes (22). Recent work from our laboratory approached this question of relative nephrotoxic potential by conducting crossover studies of the tissue accumulation pharmacokinetics of aminoglycosides in normal volunteers. A previous study with 10 volunteers showed significant differences in tissue accumulation between gentamicin and tobramycin (1). These differences were of the same order and magnitude as noted previously in patients (26). The amount of aminoglycoside in the tissue compartment appears to be related to both the magnitude and the extent of subsequent renal toxicity (23, 26). Work with tobramycin (1, 25), gentamicin (1, 23), and amikacin (8) has supported the relationship between the predicted amount of drug in the body at steady state and relative rates of nephrotoxicity. Netilmicin is an aminoglycoside antibiotic which has been widely studied in animal models (4, 9, 10, 14, 15, 18, 20), clinical trials (3, 5, 7, 12, 19, 27, 28), and pharmacokinetic studies in volunteers (6). Some studies rank the nephrotoxicity of this agent as similar to that of tobramycin (12), whereas others suggest its nephrotoxicity profile more closely resembles that of gentamicin (19, 28). Although in animals netilmicin appears to show greater tissue accumula*
MATERIALS AND METHODS Informed consent was obtained from 11 normal volunteers between the ages of 20 and 40 years. Prestudy medical histories, physical examinations, and blood screening hematology profiles, chemistries, urinalyses, 24-h creatinine clearances, and (when applicable) pregnancy tests were
performed. Dosing and blood sampling. Subjects received a 1.0-mg/kg (body weight) dose of either netilmicin or tobramycin, which was followed by a 3-month interval before the crossover phase. The drug was administered intravenously in 20 ml of normal saline over 2 to 5 min. Blood samples were collected at the following times: predose, 15 and 30 min, and 1, 1.5, 2, 4, 6, 8, 24, 48, 72, and 96 h after the injection. Additional serum samples were obtained at 120, 144, and 168 h from several subjects. Urine was collected from 0 to 4, 4 to 8, 8 to 12, and 12 to 24 h on day 1, and then 24-h urine collections were done daily for 30 days. Samples were stored frozen at -20°C until assay. Blood screening profiles and creatinine clearances were repeated on days 6 and 14 postdosing. Assays. Serum and urine samples were analyzed for netilmicin and tobramycin by radioimmunoassay (International Bioclinical, Inc., Portland, Oreg.). For drug concentrations
Corresponding author. 605
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TABLE 1. Demographic data of 11 normal volunteer subjects
Age (yr)/sex
Subject
34/Male 30/Male 29/Female 25/Male 25/Male 25/Male 25/Female 31/Female 28/Male 32/Female 36/Male
1 2 3 4 5 6 7 8 9 10 11 a
(kg)
CLCRanper (mi/mi
73.6 104.3 61.7 63.5 73.0 74.5 66.8 59.0 80.0 63.0 92.7
99 124 104 111 123 98 110 78 96 94 73
Wt
1.73 inl)
10..
Dose (mg) Tobramycin Netilmicin
105.1 117.6 64.9 73.6 77.0 74.2 74.5 50.5 83.8 64.7 106.6
75.0 110.0 64.9 64.0 75.0 70.0 70.0 65.8 87.4 64.7 105.9
CLCR, Creatinine clearance.
2.
I. 0.5 z
0.2
.
0.1
I-\ w
z
° 0.02
greater than 16 ,ug/ml or less than 1.0 ,ug/ml, assay dilutions were modified to bring the sensitivity of the method into the desired ranges. Interday and intraday coefficients of variation averaged between 3 and 7% over the concentration range of samples assayed. Pharmacokinetics. The concentrations in serum and urinary excretion rates versus time of each subject were simultaneously fitted to an open, two-compartment pharmacokinetic model by using the nonlinear curve-fitting program NONLIN (16). Because concentrations in serum were below assay sensitivity within several days of drug administration, simultaneous fitting of serum and urine data was necessary to obtain a reliable estimate of the terminal half-life (11). The parameters derived from this model were used to calculate tissue accumulation of each aminoglycoside for each subject and to predict the amount in the body at steady state (1, 16, 23, 26). Statistical analysis was performed by using a paired Student t test, with significance defined as P < 0.05. RESULTS Relevant demographic data for the 11 normal volunteers are shown in Table 1. All 11 subjects completed both phases of the trial with no significant adverse effects. Subject 7 did experience a slight burning sensation during infusion of tobramycin. There were no consistent alterations in laboratory values after administration of either netilmicin or tobra-
mycin. Subject
1 2 3 4 5 6 7 8 9 10 11
0.01. -----
0.Om. 0.002. 0.0S1
.k 190 120 140 1 60 180 a
0
20
40
60
J
a
80
TIME (hr)
FIG. 1. Simulated serum concentration-versus-time profiles for netilmicin (.... ) and tobramycin ( ). Mean values from the 11 subjects were used to create the graphs.
At the end of the 30-day postdose urine collections, an average of 101.04 ± 14% of the administered dose had been recovered in urine. The decline in concentrations in serum was biexponential for both drugs in all subjects. The data were fitted to a two-compartment model. The mean serum concentrationversus-time curves for both tobramycin and netilmicin are shown in Fig. 1. Differences in the two-compartment pharmacokinetics of tobramycin and netilmicin were apparent in the terminal phase of elimination: netilmicin had a longer serum half-life and higher postdistributive concentrations in serum. The derived pharmacokinetic parameters are shown in Tables 2 and 3. The steady-state volume of distribution was consistently, although not significantly,
TABLE 2. Two-compartment pharmacokinetic data for tobramycin in 11 normal V1 (liter/kg) k12 (h-') k2l (h-1) klo (h-1) V,, (liters/kg) 0.00980 0.358 0.07220 0.218 1.828 0.208 1.722 0.03572 0.00998 0.376 0.356 0.04374 0.984 0.01051 0.191 0.244 0.01223 0.292 0.02122 0.667 0.297 2.615 0.05508 0.00609 0.260 0.00553 0.265 0.04476 0.290 2.647 0.328 2.054 0.04822 0.01169 0.400 0.114 0.378 0.694 0.03195 0.00629 1.196 0.01046 0.283 0.04422 0.229 0.200 0.341 2.289 0.05741 0.00549 0.172 0.782 0.279 0.04432 0.01251
Mean ± SD 0.245 ± 0.085 1.589 ± 0.760 0.04535 ± 0.01352 0.00914 ± 0.00275 0.308
volunteer subjectsa CLB (mlmin) tV20 (h) 85.36 81.86 74.25 60.97 135.23 146.73 68.30 119.63 76.92 147.92 64.53
85.36 136.0 69.8 75.4 94.2 95.9 146.3 42.4 86.4 71.5 74.2
Xl) (mg) 275.8 281.0 98.5 62.7 300.3 291.8 123.3 88.1 166.0 253.5 182.1
+ 0.050 96.52 ± 33.91 89.8 ± 29.8 193.0 ± 90.6 a V1, Volume of distribution in the central compartment; VII, volume of distribution at steady state; k12, k2j, and k1o, elimination rate constants from central-peripheral compartment, peripheral-central compartment, and central compartment-urine, respectively; tV213, terminal elimination half-life; CLB, total body clearance; XI', accumulation in body at steady state.
Subject
1 2 3 4 5 6 7 8 9 10 11
Mean ± SD a
b
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VOL . 31, 1987
TABLE 3. Two-compartment pharmacokinetic data for netilmicin in 11 normal volunteer subjectsa V1 (liter/kg) k12 (h-') k2l (h-1) klo (h-1) V, (liters/kg) t1/2R (h) CLB (mlmin) 172.03 0.108 1.539 0.06506 0.00492 0.299 39.6 54.6 0.152 1.481 0.06283 0.00701 0.207 129.58 0.300 150.68 52.4 0.170 2.131 0.06477 0.00561 0.117 1.076 0.04424 0.272 149.13 33.8 0.00542 0.155 5.694 0.10452 0.237 341.45 44.8 0.00293 0.089 1.334 0.07017 0.00501 0.366 165.35 40.3 0.099 0.712 0.06018 0.346 84.28 38.1 0.00969 0.207 1.621 0.04162 0.00610 0.219 135.66 44.6 158.51 0.199 1.775 0.04082 0.00516 0.232 61.5 0.136 0.05221 0.363 107.34 51.9 1.096 0.00741 0.192 3.694 0.10634 0.00583 0.245 173.81 69.6
0.148b ± 0.041
2.014 ± 1.448
0.06480b ± 0.02247
0.00591b
0.280 ± 0.059
± 0.00171
160.71 ± 65.96
48.3 ± 10.9
XBs
422.5 620.0 318.5 248.2
1,423.2 338.9 161.0 269.7 389.2 160.4
1,047.9
490.9b ± 398.7
Parameters are defined in the footnote to Table 2. Significantly different from tobramycin at P < 0.005.
larger for netilmicin. Netilmicin showed a significantly smaller central volume of distribution (P < 0.05) and more rapid rate constants for intercompartmental distribution, as well as a longer terminal elimination half-life. Ten of the eleven subjects had a lower clearance of netilmicin than of tobramycin (P < 0.05); these data are shown in Fig. 2. The significantly longer terminal half-life of netilmicin and overall slower total body clearance reflect the observation that netilmicin showed a 2.5 times larger steady-state accumulation in the body (491 versus 193 mg for tobramycin; Tables 2 and 3). These differences were statistically significant at P < 0.05. The netilmicin pharmacokinetic parameters for these 11 volunteers were compared with values from previous patient studies (7, 25) and previous normal volunteer studies (1). Both tobramycin and netilmicin showed absolute differences between the studies in patients and volunteers (Table 4). Five of the volunteers participated in tobramycin studies in both 1979 and 1984. These volunteers had similar kinetic parameters on both occasions (Table 5). DISCUSSION Early studies with gentamicin, tobramycin, netilmicin, and amikacin proposed that aminoglycosides are similar when studied using a one-compartment pharmacokinetic model (6, 21, 28). Recent studies demonstrated significant differences between these agents when their two-compartment pharmacokinetic parameters are compared (1, 7, 8, 15, 23). The lower total body clearance for netilmicin (48 versus 90 ml/min for tobramycin) could be explained by differences in filtration or tissue binding. However, because netilmicin and tobramycin have similar molecular weights and neither is highly protein bound, it is unlikely that differences in glomerular filtration could account for the observed differences. The volunteers did not show differences in creatinine clearance, so the lower total body clearance relative to creatinine clearance reflects a more avid netilmicin reabsorption and binding in the proximal convoluted tubular cells. This binding affinity differential presumably exists in all tissues which bind aminoglycosides. Based on previous studies of postmortem tissue concentration measurement, most body tissues avidly bind aminoglycosides (24). The tobramycin volunteer data on tissue accumulation in this trial differ somewhat from those of our previous study in normal volunteers (1; Table 4). In a similar trial comparing
gentamicin and tobramycin given as 1.0-mg/kg doses to normal volunteers, Adelman et al. (1) reported significantly smaller values for tobramycin elimination rate constants from central-peripheral compartment and from peripheralcentral compartment, volume of distribution at steady state, and predicted amount in the body at steady state. Our two studies, although conducted 4 years apart, had five subjects in common. If the results for these five subjects common to both trials are compared, there are no significant differences between the predicted pharmacokinetic parameters (Table 5). This observation points to the stability of intraindividual aminoglycoside disposition, and the study differences produced by adding new volunteers to the population demonstrate the consequences of wide intersubject variability on small-sample comparisons of the multicompartment pharmacokinetics of aminoglycosides. Crossover design is
l1 1
1_ E
w z 0 < 0-J
-J
801
601
0
0
401
S
z
0
201 .
0
20
40
.
60
80
1010 1 20
1 40 1 60
TOBRAMYCIN CLEARANCE ml/min
FIG. 2. Calculated netilmicin clearance versus calculated tobramycin clearance. The line of unity is drawn for reference.
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TABLE 4. Comparison of predicted pharmacokinetic parameters with previous values from both patient and normal volunteer studiesa No. of Study drug and reference VI ssS XB (mg) CLB (ml/min) t4/21 (h) participants (liter/kg) (liters/kg) Tobramycin Schentag et al. (25) 10 0.26 1.14 129 67 200 Adelman et al. (1) 3 0.19 0.77 109 73 83 Winslade et al. (this study) 11 0.24 1.59b 96 90C 193b Netilmicin Edwards et al. (7) Winslade et al. (this study) a
11 11
0.23
1.00 2.01
O.15d
198 161
31
99
48d
491d
Parameters are defined in the footnote to Table 2.
bSignificantly different (P < 0.05) from tobramycin volunteer data of Adelman et al. (1). Significantly different (P < 0.05) from tobramycin patient data (25).
c
d Significantly different (P < 0.05) from netilmicin patient data of Edwards (7).
Subject A
Mean a
TABLE 5. Sequential pharmacokinetic parameters for five subjects given tobramycin in 1979 and again in 1984a Yr V (liters/kg) CLB (ml/min) XBS (mg/kg) V, (liter/kg) tI/20 (h) 1979 0.16 0.37 83.6 51.0 0.55 1984 0.19 0.98 74.2 69.8 1.60
B
1979 1984
0.15 0.11
0.66 0.69
129.1 119.6
56.3 42.4
1.10 1.49
C
1979 1984
0.25 0.20
0.86 2.29
114.8 147.9
76.2 71.5
1.18 4.02
D
1979 1984
0.24 0.23
0.84 1.19
113.7 76.9
88.2 86.4
1.28 2.08
E
1979 1984
0.17 0.17
0.76 0.78
112.3 64.5
95.2 74.2
1.29 1.96
1979 1984
0.193 ± 0.05 0.181 ± 0.04
0.698 ± 0.20 1.19 ± 0.65
112.7 ± 17.4
96.64 ± 35.6
73.4 ± 19.3 68.8 ± 16.1
1.08 ± 0.31 2.23 ± 1.03
+
SD"
Parameters are defined in the footnote to Table 2. = 0.43 for V1, P =0.13 for Vss, P = 0.35 for t11 , P = 0.54 for CLB, and P
b1979 versus 1984: P
essential to the evaluation of relative tissue accumulation, because it eliminates the impact of interindividual variance. Most two-compartment parameters for netilmicin are also significantly different from the patient data reported by Edwards et al. (7; Table 4). In this patient study, renal function differed from that of the volunteers, and the duration of sampling was shorter in the patient study. Netilmicin accumulates within the kidney to a much greater degree than either gentamicin or tobramycin (4, 10, 18, 20). Although this may lead to the conclusion that netilmicin is more nephrotoxic than either gentamicin or tobramycin, most animal studies indicate that netilmicin appears to cause little nephrotoxicity when compared with similar doses of gentamicin or tobramycin (10, 14, 15, 18, 20). In humans, the reported incidence of netilmicin-induced renal dysfunction varies greatly (3, 5, 12, 27). Values range from 3% (12) to 38% (3). In these studies, netilmicin does not appear to be more nephrotoxic than tobramycin. Thus, its 2.5-foldgreater tissue accumulation does not predict a 2.5-foldgreater degree of clinical nephrotoxicity. Whenever one parameter (such as tissue accumulation) does not explain all facets of a problem such as relative aminoglycoside nephrotoxicity, then other factors (such as intracellular toxicity) must be considered. Intracellular damage to various organelles or sites has been extensively studied but also does not precisely rank these drugs. Thus, it seems necessary to account for nephrotoxicity as an event partially dependent on tissue accumulation and partly depen-
=
0.06 for X'SB.
dent on potency in the production of intracellular damage. One possibility is that surface binding or cellular uptake is greater for netilmicin, while netilmicin has lower potency against the intracellular site(s) of nephrotoxicity. Although data on the relative toxicity of netilmicin in lysosomes (17, 29), mitochondria (2), and phospholipid binding sites (13) favor a lesser toxic potential for netilmicin than gentamicin at these sites, netilmicin invariably appears similar to tobramycin. LITERATURE CITED 1. Adelman, M., E. Evans, and J. J. Schentag. 1982. Twocompartment comparison of gentamicin and tobramycin in normal volunteers. Antimicrob. Agents Chemother. 22:800-804. 2. Bendirdjian, J. P., J. P. Fillastre, and B. Foucher. 1980. Mitochondrial modification with the aminoglycosides, p. 325-354. In A. Whelton and H. Neu (ed.), The aminoglycosides. Marcel Dekker, Inc., New York. 3. Bock, B. V., P. H. Edelstein, and R. D. Meyer. 1980. Prospective comparative study of efficacy and toxicity of netilmicin and amikacin. Antimicrob. Agents Chemother. 17:217-225. 4. Brier, M. E., P. R. Mayer, R. A. Brier, D. Visscher, F. C. Luft, and G. R. Aronoff. 1985. Relationship between rat renal accumulation of gentamicin, tobramycin, and netilmicin and their nephrotoxicities. Antimicrob. Agents Chemother. 27:812-816. 5. Buckwold, F. J., A. R. Ronald, B. Lank, L. Thompson, C. Rox, and G. K. M. Harding. 1979. Clinical efficacy and toxicity of netilmicin in the treatment of gram-negative infections. Can. Med. Assoc. J. 120:161-167. 6. Chung, M., R. Costello, and S. Symchowicz. 1980. Comparison
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