Vol. 34, No. 10

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 1990, p. 1944-1948

0066-4804/90/101944-05$02.00/0 Copyright © 1990, American Society for Microbiology

Pharmacokinetics and Dose Proportionality of Cefmetazole in Healthy Young and Elderly Volunteers MARIE T. BORIN,l* GARY R. PETERS,2'3 AND THOMAS C. SMITH2'3 Clinical Pharmacokinetics,l Clinical Pharmacology,2 and Upjohn Research Clinics,3 The Upjohn Company, Kalamazoo, Michigan 49001 Received 20 April 1990/Accepted 10 August 1990

The pharmacokinetics and dose proportionality of cefmetazole were studied in 24 healthy volunteers (12 and 12 elderly). Each volunteer received single 0.5-, 1-, and 2-g doses of cefmetazole administered intravenously over 5 min according to a three-way crossover design. Serial plasma and urine samples were collected over a 24-h period following dosing and assayed for cefmetazole by a high-performance liquid chromatography method. Results of the dose proportionality portion of the study indicated that cefmetazole pharmacokinetics are linear and proportional with dose in both age groups. Comparisons of pharmacokinetic parameters between the young and elderly groups indicated that the systemic clearance was significantly lower in elderly than in young volunteers (92.4 versus 112 ml/min). Additionally, creatinine clearance was significantly lower in elderly (74.1 ml/min) than in young (92.9 ml/min) subjects. No significant differences between age groups were observed for volume of distribution, urinary recovery, terminal half-life, nonrenal clearance, or renal clearance, although half-life was slightly prolonged in elderly volunteers relative to that in young volunteers (1.54 versus 1.34 h), and renal clearance was slightly lower in elderly than in young volunteers (83.7 versus 96.1 ml/min). Both systemic and renal clearance were significantly correlated with creatinine clearance. These results indicate that the observed age-related differences in the pharmacokinetics of cefmetazole are most likely due to differences in renal function between the two age groups. The small reduction in cefmetazole elimination in the elderly would not warrant dose adjustment in this population. young

Cefmetazole sodium is a parenteral cephamycin antibiotic having a broad antibacterial spectrum in vitro which includes many strains of both gram-positive and gram-negative aerobic and anaerobic bacteria (6, 12, 14, 19, 21). Clinical studies have shown its effectiveness in the treatment of a number of infections and in prophylactic use prior to surgery (8, 19, 23). Pharmacokinetic studies of healthy young volunteers following intravenous administration of cefmetazole sodium have demonstrated that cefmetazole is eliminated primarily by renal mechanisms resulting in greater than 70% recovery of intact cefmetazole in urine (13, 15). Cefmetazole pharmacokinetics have also been studied in patients with various degrees of renal insufficiency (13, 20). In these patients, the elimination half-life of cefmetazole was found to increase progressively with decreasing renal function. Physiological changes associated with aging which can affect drug disposition include decreases in lean body mass and body water and an increase in body fat, which can result in altered drug distribution, and a decrease in serum albumin levels, which can lead to changes in drug binding (7, 26). Reductions in glomerular filtration rate and renal tubular function in the elderly are also well documented and can result in decreased elimination of drugs which are primarily renally excreted (5, 24). Therefore, the present study was conducted to determine whether the pharmacokinetics of cefmetazole in healthy elderly volunteers differ from those in healthy young subjects. A second objective was to determine whether cefmetazole pharmacokinetics following intravenous infusion are linear and proportional with dose in these two groups of subjects.

*

MATERIALS AND METHODS Subjects. Twelve healthy young and twelve healthy elderly

normal volunteers participated in the study. Volunteers in the young group ranged in age from 21 to 40 years and in body weight from 49.1 to 96.8 kg. The age and weight ranges of volunteers in the elderly group were 65 to 78 years and 48.6 to 88.6 kg. Six males and six females were enrolled in each of the age groups. Subjects were chosen for participation in the study after giving their written informed consents and medical histories and receiving complete physical exams, electrocardiograms, and clinical laboratory tests. Subjects were excluded from the study if they had histories or evidence of unstable or serious disorders of the nervous, cardiovascular, hepatic, renal, or hematological systems, allergic reactions to beta-lactam antibiotics or had taken investigational drugs within 3 months of the start of the study. Additionally, subjects refrained from alcohol consumption for 24 h prior to each study day and during the study and did not take any acute or chronic medications during the study period. Drug administration. Each subject received a single intravenous dose of each of the following cefmetazole sodium treatments in a randomized crossover fashion, with 1 week between treatments: 0.5, 1, and 2 g (cefmetazole acid equivalents). Each treatment was administered intravenously in a total volume of 27 ml over a 5-min period via a Razel infusion pump.

Sample collection. Blood samples (7 ml) were obtained via lock from the arm opposite the drug infusion site at the following times after the start of infusion: 0 (prior to dosing), 0.17, 0.33, 0.67, 1, 2, 3, 4, 6, 8, 10, 12, and 16 h. Plasma was harvested from each sample, quick-frozen, and stored at -20°C until assayed. Urine specimens were collected prior to dosing (-24 to 0 h) and at 0-to-12- and 12-to-24-h intervals following each dose. Subjects were a heparin

Corresponding author. 1944

VOL. 34, 1990

CEFMETAZOLE PHARMACOKINETICS IN THE YOUNG AND ELDERLY

instructed to void all urine immediately prior to each dose and to include that urine with the previous collection. Following each void, urine specimens were kept on ice until the end of the collection interval. After thorough mixing of all urine from a collection interval, urine volumes were recorded, and 15-ml samples were stored frozen (-20°C) until assayed for cefmetazole concentrations. The 24-h creatinine clearance (CLCR) was determined with a sample of the -24-to-0-h urine collection and a midpoint plasma sample obtained prior to the first phase of the study. Sample analysis. Concentrations of cefmetazole in plasma and urine were determined by an automated reversed-phase high-performance liquid chromatography method which uses a Zymark Zymate II robot (4). In brief, samples were mixed and deproteinized, an internal standard (barbital) was added, and samples were vortexed, centrifuged, and finally injected onto a C18 column by the robot. The mobile phase consisted of 0.02 M citrate buffer (pH 5.4)-acetonitrile (88:12, vol/vol), and the flow rate was maintained at 1.5 ml/min. Column eluate was monitored with a UV detector (254 nm), and quantitation was achieved by using peak height ratios. The lower limits of quantitation were 2 and 15 ,ug/ml in plasma and urine, respectively. Cefmetazole standard curves in plasma were linear over the calibration range of 2.0 to 201.6 ,ug/ml with correlation coefficients greater than 0.9940 (n = 17) and within-run slope coefficients of variation ranging from 0.12 to 3%. Assay precision, expressed as the coefficient of variation of estimated concentrations of quality control samples, ranged

100

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0.1

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Time (hr)

FIG. 1. Cefmetazole concentrations (mean + standard deviation) in plasma of young (a) and elderly (b) subjects following a 0.5-g (circles), 1-g (squares) or 2-g (triangles) 5-min intravenous infusion.

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TABLE 1. Summary of subject demographics and CLCRa Groupb

Young Elderly

Age (yr)c

30.5 68.9

+ +

5.4 3.8

Wt (kg)

68.0 ± 15.2 72.2 + 13.8

Ht (cm)

169.3 166.7

+ +

6.5 10.6

CLCR (ml/min)'

92.9 + 15.7 74.1 ± 20.8

a Data are presented as mean + standard deviation. b Each group consisted of six males and six females. Pp < 0.05, young versus elderly.

from 1.6 to 11, 0.4 to 15, and 0.3 to 8%, respectively, for low (6.75 ,ug/ml), medium (33.7 p,g/ml), and high (120.5 ,ug/ml) concentrations. Assay accuracy, the ratio of estimated to theoretical quality control concentrations, ranged from 88.9 to 143, 88.4 to 107, and 91 to 101.4%, respectively, for the low, medium, and high cefmetazole concentratons. Overall mean recovery of cefmetazole from plasma was 98% + 11%. In urine, cefmetazole standard curves were linear over the calibration range of 0.015 to 1.035 mg/ml with correlation coefficients of 0.9997 or greater and within-run slope coefficients of variation ranging between 0.3 and 0.9%. Assay precision ranged from 0.6 to 4, 0.23 to 5, and 0.17 to 5%, respectively, for low (0.064 mg/ml), medium (0.31 mg/ml), and high (0.63 mg/ml) concentrations. Assay accuracy ranged from 100 to 112, 96.3 to 104.7, and 97.5 to 108%, respectively, for low, medium, and high cefmetazole concentrations. Overall mean recovery was 103% + 4%. Pharmacokinetic analysis. Pharmacokinetic analysis of plasma concentration-time data was performed by noncompartmental methods (11). Terminal elimination rate constants (kel) were estimated by nonlinear regression analysis of cefmetazole plasma concentration-time data by using RSTRIP (9). Elimination half-life was calculated as 0.693/kel. Areas under the plasma concentration-time curve (AUCO T) and under the first moment of the concentration-time curve from time zero to T, the time of the last detectable sample concentration, were calculated by the trapezoidal rule. Both terms were extrapolated to infinity. Systemic clearance (CLp) was estimated by dividing the dose by AUC,. Mean residence time (MRT) and apparent volume of distribution (Vss) were calculated by using statistical moments (2). Urinary excretion of cefmetazole was determined by multiplying urine concentrations by the corresponding urine volume values. Cumulative urinary excretion (A.) was determined by summing the amounts of drug excreted in the 0-to-12- and 12-to-24-h collection intervals. The fraction of the administered dose excreted in the urine (Fe) was calculated as Au divided by the dose. Renal clearance (CLR) was determined by dividing Au by AUC,,. Cefmetazole nonrenal clearance (CLNR) was calculated by subtracting CLR from CLp. Statistical analysis. Differences in pharmacokinetic parameters among treatments (doses) were investigated in young and elderly subjects separately by the general linear models procedure of the Statistical Analysis System (version 5) for a mixed-effects analysis of variance model with the group, period, and treatment as fixed effects and the subjects within a group as a random effect. Assumptions inherent in applying this analysis of variance procedure were verified by distributional analyses and Bartlett's test for equality of variances. The Waller-Duncan K-ratio t test was used for pairwise comparisons of treatment means. Correlations between selected pharmacokinetic parameters and dose or CLCR were investigated by simple least-squares regression analysis. If the intercept term was not significantly different from zero (P > 0.05), the regression line was forced through

BORIN ET AL.

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ANTIMICROB. AGENTS CHEMOTHER. TABLE 2. Cefmetazole pharmacokinetic parameters'

drose

Dose-normalized

(AUg

(rig h/mi)

(ml/min)b

83.1 (19.3) 151 (29.8) 301 (60.4)

83.1 (19.3) 75.5 (14.9) 75.2 (15.1)

105 (25.1) 116 (29.7) 116 (26.9)

99.4 (32.6) 186 (52.3) 387 (111)

99.4 (32.6) 92.9 (26.1) 96.6 (29.3)

(g)

h/mi)

Young 0.5 1 2

Vss (liters)

MRT

(h)'

kei (h-1)

t112 (hY'

Fe

ClR

CLNR

11.0 (4.1) 1.82 (0.95) 0.534 (0.155) 11.9 (4.2) 1.70 (0.22) 0.485 (0.085) 12.3 (3.1) 1.81 (0.49) 0.534 (0.139)

1.30 1.43 1.30

0.92 (0.17) 97.1 (28.2) 10.7 (15.9) 0.82 (0.17) 96.3 (34.8) 19.2 (17.4) 0.83 (0.19) 94.6 (34.1) 18.1 (18.8)

90.4 (22.7) 10.6 (3.0) 2.02 (0.51) 0.496 (0.156) 95.2 (22.9) 12.6 (3.6) 2.25 (0.50) 0.416 (0.120) 91.5 (20.4) 12.4 (2.5) 2.33 (0.54) 0.434 (0.096)

1.40 1.67 1.60

0.96 (0.15) 88.0 (32.0) 6.42 (10.0) 0.88 (0.09) 85.5 (26.9) 10.1 (6.41) 0.84 (0.11) 77.6 (22.6) 14.0 (10.8)

Elderly 0.5 1 2

a Data are presented as mean (standard deviation). b p < 0.05, 0.5-g dose verus 1- or 2-g dose in young group. Pp < 0.05, 0.5-g dose versus 1- or 2-g dose in elderly group. d 112, Half-life; harmonic mean. e P < 0.05, 0.5-g dose versus 1- or 2-g dose in young and elderly groups.

the origin. Comparisons of pharmacokinetic parameters for young and elderly volunteers were made by using the general linear models procedure with a mixed-effects analysis of variance model with age, treatment, and an age-by-treatment interaction term as fixed effects and subject within age as a random effect. For all pharmacokinetic parameters, the treatment-by-age interaction was not statistically significant, which indicated that the shapes of the parameter-versus-age curves were not different among treatments, allowing for valid statistical comparisons between age groups and among treatments.

RESULTS Demographics. A summary of subject demographic data is provided in Table 1. There were no statistically significant differences in body weight between the age groups. As expected, CLCR in the elderly was significantly lower (P < 0.05) than that in the young subjects. Linearity and dose proportionality. Mean plasma concentration-time profiles for the young volunteers are depicted in Fig. la, and average cefmetazole pharmacokinetic parameters are given in Table 2. No statistically significant differences among treatments for Vs, MRT, or kei were observed, indicating that dose had no effect on cefmetazole disposition. Mean CLp following the 0.5-g dose was found to be slightly but significantly lower (9%) than CLp for the 1- or 2-g dose. was about 10% Analogously, dose-normalized AUC higher after the 0.5-g dose than following the higher doses. Urinary recovery was significantly higher following a 0.5-g dose as compared with the 1- or 2-g dose. CLR and CLNR did not differ among doses. Linear regression analyses of AUCO, versus dose revealed a statistically significant (P < 0.0001) relationship between these variables in young volunteers: AUC = 0.151 * dose, r 0.919. A significant (P < 0.0001) correlation _

=

between Au and dose was also observed: Au = 0.833 dose, r = 0.906. Mean plasma concentration-time profiles for elderly volunteers are shown in Fig. lb, and average cefmetazole pharmacokinetic parameters are provided in Table 2. There were no statistically significant differences among treatments for CLp, dose-normalized AUC X, V,,,, and kel. A significant (P < 0.05) difference in MRT among treatments was observed, with mean MRT following the 0.5-g dose being 13% lower than that following the 2-g dose. Since MRT reflects both distribution and elimination processes and no difference in elimination rate was observed between the 0.5- and 2-g doses, the observed increase in MRT could be due to differences in cefmetazole distribution. As was observed in the young volunteers, Fe was significantly higher following a 0.5-g dose than it was after the 1- or 2-g dose. There was no statistically significant difference in CLR among treatments; however, CLNR was significantly lower following the 0.5-g dose than after the 1- or 2-g dose. Linear regression analysis of AUC -O, versus dose in elderly volunteers resulted in a significant (P < 0.0001) relationship between these variables: AUC = 0.192 * dose, r = 0.853. A significant (P < 0.0001) linear relationship between Au and dose in elderly volunteers was also observed: Au = 0.857 dose, r = 0.963. Effects of age. Dose-independent pharmacokinetic parameters and dose-normalized AUCQ;. averaged across all dose groups in elderly and young volunteers are listed in Table 3. Statistically significant differences in CLp and MRT between elderly and young subjects were observed. CLp was 18% lower and MRT was 25% higher in elderly than in young subjects. Although not statistically significant, the difference in kel between age groups resulted in a mean half-life in the elderly group which was approximately 15% longer than that in young volunteers. Fe and CLNR values were significantly -

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TABLE 3. Cefmetazole pharmacokinetic parameters averaged across all dose groups'

Group

Dose-normalized (p.g . h/mi)AUC)_.

Young Elderly

77.9 (16.5) 96.4 (28.8)

CLp (ml/min)6 112 (26.9) 92.4 (21.5)

a Data are presented as mean (standard deviation). b p < 0.05, elderly versus young groups. ' 1/2, Half-life; harmonic mean. d p < 0.05 for treatment effect.

V, (liters) 11.7 (3.75) 11.9 (3.12)

MRT

(h)b

1.73 (0.62) 2.16 (0.52)

kei (h-')

t12 (h)'

Fed

(mi/mmn)

CLR

CLNR d (ml/min)

0.518 (0.128) 0.449 (0.128)

1.34 1.54

0.86 (0.18) 0.90 (0.13)

96.1 (31.4) 83.7 (27.0)

15.9 (17.2) 10.2 (9.53)

CEFMETAZOLE PHARMACOKINETICS IN THE YOUNG AND ELDERLY

VOL. 34, 1990 a 200-

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Creatinine Clearance (ml/min) FIG. 2. Correlation between CLp (a) or CLR (b) and CLCR. CLp = 1.20 * CLCR, r = 0.522, P < 0.0001; CLR = 1.06 * CLCR, r = 0.443, P < 0.0001.

different with respect to treatment, which is consistent with the previous analyses of variance conducted in each age group separately. Because of the difference in mean CLCR between the two age groups, the correlations between several pharmacokinetic parameters (CLp, kel, and CLR) and CLCR were investigated by linear regression analysis. No significant correlation (P = 0.71) was found between ke1 and CLCR. However, cefmetazole CLp and CLR were both found to be positively correlated with CLCR (Fig. 2).

DISCUSSION Cefmetazole pharmacokinetic parameters in young volunteers following 0.5-, 1-, and 2-g doses were consistent with previously reported values (13, 15, 22). A small but statistically significant increase (9%) in CLp was observed between the 0.5-g dose and the two higher doses in young volunteers in the present study. Similarly, the urinary recovery of unchanged cefmetazole was about 10% higher following the 0.5-g dose than that following either the 1- or 2-g dose, which could be due to saturation of tubular secretion of cefmetazole at higher doses. However, the magnitude of this difference, taken in concert with the fact that the values of these parameters remained constant in the 1- and 2-g dose range, indicates that it should be regarded as a slight departure from linearity at lower doses which lacks any clinical significance, particularly since cefmetazole is typically administered as a 1- or 2-g dose. Differences among doses for average V.s, MRT, k,1, CLR, and CLNR were not significant. Linear

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relationships between AUC or A. and dose were observed, with correlation coefficients greater than 0.90. Dose proportionality and linearity were also observed in the pharmacokinetics of cefmetazole in elderly volunteers. However, as was seen in the young group, urinary recovery of cefmetazole slightly decreased as the dose increased from 0.5 to 1 or 2 g. Comparisons of cefmetazole pharmacokinetic parameters between the two age groups revealed that CLp was significantly lower and MRT was significantly longer in elderly than in young volunteers. CLR in elderly volunteers was 13% lower than that in young subjects, and cefmetazole half-life in the elderly (1.54 h) was prolonged relative to that in young volunteers (1.34 h). These differences were not statistically significant and are not likely to be clinically relevant. It has been reported that the terminal disposition rate, CLp, and CLR of cefmetazole decline as renal function diminishes (13). Since mean CLCR was lower in the elderly volunteers than in the young subjects, the pharmacokinetic differences observed between these age groups are probably due to an age-related decrease in renal function. Both CLp and CLR were found to be significantly correlated with CLCR and the slopes of these regressions were similar to those observed in patients with renal impairment (13). These correlations further demonstrate the relationship between cefmetazole CLp or CLR and renal function. Dose proportionality and linearity in the pharmacokinetics of cefmetazole are consistent with pharmacokinetic characteristics of other cephalosporins which are not highly protein bound (1, 3). Additionally, the changes observed in the disposition of cefmetazole in the elderly are similar to those reported for other cephalosporins which are predominantly excreted renally (10, 16-18, 25). In conclusion, the pharmacokinetics of cefmetazole were found to be linear and proportional with dose in both elderly and young volunteers. Urinary recovery diminished slightly as the dose increased in both groups of subjects; however, urinary recovery was not significantly different between 1and 2-g doses, the usual clinical dosages. Differences observed in cefmetazole plasma clearance between young and elderly subjects were most likely due to differences in renal function between the two groups. The small reduction in cefmetazole elimination in the elderly would not warrant dose adjustment in this population. ACKNOWLEDGMENTS We gratefully acknowledge E. L. Adkins and the staff at Upjohn Research Clinics for their technical assistance. LITERATURE CITED 1. Balant, L., P. Dayer, and R. Auckenthaler. 1985. Clinical pharmacokinetics of the third generation cephalosporins. Clin. Pharmacokinet. 10:101-143. 2. Benet, L. Z., and R. L. Galezzi. 1979. Noncompartmental determination of the steady-state volume of distribution. J. Pharm. Sci. 68:1071-1074. 3. Bergan, T. 1987. Pharmacokinetic properties of the cephalosporins. Drugs 34:89-104. 4. Bothweli, W. M., and P. A. Bombardt. 1989. An on-line column-

switching high-performance liquid chromatographic procedure

for the removal of probenecid from human plasma, serum, or urine in the quantitative determination of cefmetazole or cefoxitin. J. Pharm. Biomed. Anal. 7:987-995. 5. Cockcroft, D. W., and M. H. Gault. 1976. Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41. 6. Cormick, N. A., N. V. Jacobus, and S. L. Gorbach. 1987. Activity of cefmetazole against anaerobic bacteria. Antimicrob. Agents

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Chemother. 31:2010-2012. 7. Dawling, S., and P. Crome. 1989. Clinical pharmacokinetic considerations in the elderly. Clin. Pharmacokinet. 17:236-263. 8. DiPiro, J. T., L. S. Welage, B. A. Levine, P. E. Wing, J. A. Stanfield, H. V. Gaskill, D. S. Scarfoni, J. J. Schentag, T. A. Bowden, Jr., and J. S. Williams. 1989. Single-dose cefmetazole versus multiple dose cefoxitin for prophylaxis in abdominal surgery. J. Antimicrob. Chemother. 23(Suppl. D):55-60. 9. Fox, J. L., and M. L. Lamson. 1986. RSTRIP: pharmacokinetic data stripping/least squares parameter optimization. MicroMath Inc., Salt Lake City, Utah. 10. Garcia, M. J., A. Garcia, M. J. Nieto, A. Dominquez-Gil, G. Alonso, and L. Mellado. 1980. Disposition of cefoxitin in the elderly. Int. J. Clin. Pharmacol. Ther. Toxicol. 18:503-509. 11. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed, p. 409417. Marcel Dekker, Inc., New York. 12. Goto, S., M. Ogawa, A. Tsuji, Y. Kaneko, and S. Kuwahara. 1978. Bacteriological evaluation of a new cephamycin substance CS-1170 comparison with antibacterial action of cephalosporins and cefoxitin. Chemotherapy 26(Suppl. 5):1-20. 13. Halstenson, C. E., D. R. P. Guay, J. A. Opsahl, C. A. I. Hirata, L. S. Olanoff, E. Novak, H. Ko, K. S. Cathchrt, and G. R. Matzke. Disposition of cefmetazole in healthy volunteers and patients with impaired renal function. Antimicrob. Agents Che-

mother. 34:519-523. 14. Jones, R. N., A. L. Barry, P. C. Fuchs, and C. Thornsberry. 1986. Antimicrobial activity of cefmetazole (CS-1170) and recommendations for susceptibility testing by disk diffusion, dilution, and anaerobic methods. J. Clin. Microbiol. 24:1055-1059. 15. Ko, H., K. S. Cathcart, D. L. Griffith, G. R. Peters, and W. J. Adams. 1989. Pharmacokinetics of intravenously administered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimination. Antimicrob. Agents Chemother. 33:356-361. 16. Ljungberg, B., and I. Nilsson-Ehle. 1987. Pharmacokinetics of antimicrobial agents in the elderly. Rev. Infect. Dis. 9:250-264. 17. Ljungberg, B., and I. Nilsson-Ehle. 1988. Influence of age on the pharmacokinetics of ceftazidime in acutely ill, adult patients. Eur. J. Clin. Pharmacol. 34:173-178.

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18. Ludwig, E., E. Szekel, A. Csiba, and H. Graber. 1988. Pharmacokinetics of cefotaxime and desacetyl-cefotaxime in elderly patients. Drugs 35(Suppl. 2):51-56. 19. Nakao, H., H. Yanagisawa, B. Shimizu, M. Kaneko, M. Nagano, and S. Sugawara. 1976. A new semisynthetic 7a-methoxycephalosporin, CS-1170: 7,-[[(cyanomethyl)thio]acetamido]-7amethoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem4-carboxylic acid. J. Antibiot. 29:554-558. 20. Ohkawa, M., M. Orito, T. Sugata, M. Shimamura, M. Sawaki, E. Nakashita, K. Kuroda, and K. Sasuhara. 1980. Pharmacokinetics of cefmetazole in normal subjects and in patients with impaired renal function. Antimicrob. Agents Chemother. 18: 386-389. 21. Ohm-Smith, M. J., and R. L. Sweet. 1987. In vitro activity of cefmetazole, cefotetan, amoxicillin-clavulanic acid, and other antimicrobial agents against anaerobic bacteria from endometrial cultures of women with pelvic infections. Antimicrob. Agents Chemother. 31:1434-1437. 22. Rodriguez-Barbero, J., E. L. Marifio, and A. Dominguez-Gil. 1985. Pharmacokinetics of cefmetazole administered intramuscularly and intravenously to healthy adults. Antimicrob. Agents Chemother. 28:544-547. 23. Rodriguez-Barbero, J. R., E. L. Marifio, M. J. Otero, J. R. Commes, J. Garcia, J. M. Rodriguez, F. Lozano, A. DominguezGil, and A. G6mez-Alonso. 1984. Concentrations of cefmetazole in plasma and tissue resulting from peri-incisional administration before appendectomy. Antimicrob. Agents Chemother. 26:787-788. 24. Rowe, J. W., R. Andres, J. D. Tobin, A. H. Norris, and N. W. Shock. 1976. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J. Gerontol. 31:155-163. 25. Sugihara, H., K. Yoneyama, H. Sorimachi, T. Kamo, S. Imamura, N. Akashi, M. Yamada, and T. Shimizu. 1988. Pharmacokinetics of cefotaxime in elderly patients. Drugs 35(Suppl. 2):93-96. 26. Woodhouse, K. W., and H. Wynne. 1987. The pharmacokinetics of nonsteroidal anti-inflammatory drugs in the elderly. Clin. Pharmacokinet. 12:111-122.

Pharmacokinetics and dose proportionality of cefmetazole in healthy young and elderly volunteers.

The pharmacokinetics and dose proportionality of cefmetazole were studied in 24 healthy volunteers (12 young and 12 elderly). Each volunteer received ...
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