ANTimUcRoBiAL AGzNTs AND CHEMOTHERAPY, July 1977, p. 73-79 Copyright © 1977 American Society for Microbiology

Vol. 12, No. 1 Printed in U.S.A.

Metabolic Fate of [14C]Cefamandole, a Parenteral Cephalosporin Antibiotic, in Rats and Dogs H. R. SULLIVAN,* S. L. DUE, D. L. K. KAU, J. F. QUAY, AND W. M. MILLER The Lilly Research Laboratories, Indianapolis, Indiana 46206

Received for publication 2 December 1976

The biotransformation of the parenterally effective cephalosporin antibiotic cefamandole nafate (I) has been studied in rats and dogs. After rapid in vivo hydrolysis of the nafate pharmaceutical form to cefamandole (II), the antibiotic was found to be very resistant to metabolic degradation in both species. In dogs, cefamandole escaped metabolism and was eliminated as unaltered antibiotic almost exclusively by renal excretion. In rats, cefamandole was somewhat labile to metabolism; however, a major portion of the administered antibiotic was eliminated unchanged principally by renal excretion. vivo so that in humans approximately 90% of the area under the plasma level curve is due to cefamandole (13). The hydrolysis of cefamandole nafate (I) to cefamandole (II) can also occur in blood or urine in vitro so that intact cefamandole nafate (I) would not be observed unless precautions are taken to present further hydrolysis. In these animal metabolism studies crystalline [14C]cefamandole nafate (I) was first dissolved in 1.67% sodium carbonate solution and then allowed to stand at ambient temperature for 15 min to closely approximate the reconstituted clinical preparation. Thin-layer chromatographic analysis showed this solution to consist of a 1:1 mixture of [14C]cefamandole nafate (I) and [14C]cefamandole (II). This solution was then diluted to the desired concentration with isotonic saline solution (pH 7.1) for administration to animals. MATERIALS AND METHODS [14C]cefamandole nafate (I), 7-D-[1-_4C]mande-

Cefamandole, 7-D-mandelamido-3-{[(1methyl - 1H - tetrazol - 5 - yl) - thio]methyl} - 3 cephem4-carboxylic acid, sodium salt (II) is a new semisynthetic, parenteral cephalosporin antibiotic. Cefamandole possesses a broad spectrum of antibiotic activity against a variety of gram-positive organisms, including penicillinresistant strains, and many gram-negative organisms, including Haemophilus influenzae (1, 5, 7, 14). Cefamandole is significantly more resistant to hydrolysis by beta-lactamase-producing bacteria than are other cephalosporin antibiotics (7, 8, 14). Clinical pharmacokinetic studies have shown that concentrations of cefamandole in the serum after parenteral injection of the antibiotic exceed manyfold the minimal inhibitory concentrations for a great majority of the bacteria studied (2). Metabolism studies here described, patterned after earlier studies (9-12), show cefamandole after intravenous (i.v.) administration to be resistant to metabolic degradation or alteration. As in earlier studies from these laboratories, radiocarbon labeling was used to facilitate the present investigation. Cefamandole nafate (I), the formyl ester of cefamandole (II), was chosen as the pharmaceutical form of this cephalosporin antibiotic because of its crystallinity and resulting dry state stability (3) (Fig. 1). It is readily converted to cefamandole in vitro in a pH-dependent reaction (3). The hydrolysis of the formyl moiety begins upon solution in water and is facilitated by the presence of Na2C03. The pharmaceutical preparation of cefamandole nafate (I) used in clinical investigations contains 63 mg of N2CO3 per g of cefamandole (II) activity. The hydrolysis of cefamandole nafate (I) to cefamandole (II) continues rapidly in

lamido-3-{[(1-methyl-lH-tetrazol-5-yl)thio]methyl}-

3-cephem4-carboxylic acid formate ester, sodium salt. Thionyl chloride, 267 ILI, was added dropwise to a slurry of 114 mg (0.75 mmol, 8.27 ,uCi/mmol; New England Nuclear Corp.) of D_(-)-[1-14C]mandelic acid ([a]5 = - 140.5°) and 114 mg (0.75 mmol) of n(-)-mandelic acid [a]25 = - 149.0°) in 561 ,ul of 97 to 100% formic acid. After complete addition, the resulting solution was stirred at ambient temperature for 4 h. The reaction solution was concentrated in vacuo at 45°C to yield a colorless oil. The product was dissolved in benzene, and the resulting solution was evaporated to dryness in vacuo. This procedure was repeated three times. The residual oil was redissolved in 3 ml of benzene, and 267 ,lA of thionyl chloride was added. The resulting solution was heated at reflux temperature for 2 h and then concentrated to dryness in vacuo at 45°C. The residual 73

74

ANTIMICROB. AGENTS CHEMOTHER.

SULLIVAN ET AL. 0

O-C-HO &-1H_'tNH

CH XN

CH,_

COONa+

OH

N-NJ~,J

aq.

N,

CH3

0

CH-14S-NH wN

N

O

COONae

CH3

FIG. 1. Structure of cefamandole nafate (I) and cefamandole (II).

oil, n-(-)[1-14C]mandelic acid chloride, 0-formyl ester, was redissolved in 3 ml of benzene, and the resulting solution was concentrated to dryness in vacuo three times. A solution consisting of 448 mg (1.36 mmol) of 3-

{[(1-methyl-1H-tetrazol-5-yl)thio]methyl)-3-cephem-

4-carboxylic acid and 893 mg (6.82 mmol) of N-trimethylsilylacetamide in 6 ml of chloroform was heated at reflux temperature with stirring for 30 min. The reaction mixture was cooled to 20°C, and a solution of -(-)[1-14C]mandelic acid chloride, 0-formyl ester, in 3 ml of dichloromethane was added dropwise with stirring. The resulting mixture was stirred for 16 h at ambient temperature and then poured into 75 ml of ethyl acetate. The organic solution was washed successively with 25 ml of water and 25 ml of n-saline solution. The organic solution was decolorized by treatment with activated charcoal, filtered, and dried over anhydrous sodium sulfate. After filtration, the organic solution was concentrated to dryness in vacuo at 45°C to yield a residue of 672 mg (1.36 mmol) of crude product. This product was dissolved in 5 ml of toluene, and 288 mg (1.70 mmol) of sodium 2-ethylhexanoate was added. The mixture was swirled until complete solution was attained. Within 5 min crystals of product began to appear, and after 2 h at ambient temperature the solution was placed in a freezer for 16 h. Crystallized [14C]cefamandole nafate (I) was collected by filtration and was washed with acetone. The yield of purified, radiocarbonlabeled antibiotic was 0.71 mmol (52%), with a specific activity of 7.24 ,uCi/mg. Paper chromatography followed by microbiological and radiological assay showed the product to be pure. Chromatographic methods. Paper chromatography was carried out on Whatman no. 4 paper, and a methyl ethyl ketone-water (92:8) solvent system was used for development. Areas of biological activity were located by using the bioautographic technique previously described by Miller (6), using Bacillus subtilis. Zones of radioactivity were located by use of a radiocarbon scanner (Vanguard 880 automatic chromatogram scanner).

Thin-layer chromatography was carried out using Silica Gel F (E. Merck AG, Darmstadt, Germany) plates. The separation of [14C]cefamandole (Rf 0.55), cefamandole nafate (Rf 0.63), and two metabolites (Rf 0.66 and 0.81) was accomplished using an ethylacetate-acetone-acetic acid-water (50:20:20:10) solvent system for development. Sample preparations for microbiological assay. Samples of urine, bile fluid, plasma, and other biological fluids were adjusted to pH 6.0 by addition of 0.5 M Na2HPO4 solution immediately after collection. Dilutions were made as required using pH 6.0 aqueous buffer containing, in milliequivalents per liter: Na+, 160; Cl-, 150; P043-, 5; and AcO-, 4.4. Standard solutions of cefamandole containing 0.025 to 1 ,tg/ml were prepared in buffer on the day of the test. Whole-blood samples were frozen and thawed to effect hemolysis. One part, by volume, of hemolyzed blood was diluted with 2 volumes ofthe pH 6.0 buffer described above. Standard solutions of cefamandole were prepared on the day of the test in a compound diluent composed of 1 volume of hemolyzed blood and 2 volumes of pH 6.0 buffer. When further dilutions were required, the same compound diluent was used. Microbiological assay. Cefamandole antibacterial activity in biological fluid samples was compared to that in previously prepared standard solutions using a disk-plate agar diffusion test against B. subtilis derived from ARCC 6633 (the inoculum was 19%, by volume, of a 10% light transmission spore suspension) grown in BBL agar no. 1, pH 6.6, at 37°C. Zone diameters for diluted samples were compared to zone diameters produced by standard concentrations of cefamandole-free acid in buffer. Apparent concentrations of cefamandole in samples were corrected for the effect of biological fluid on the assay response by comparison with samples of control fluid containing known concentrations of the antibiotic. Elimination studies, rats. Animals used in these studies were albino male rats, Purdue-Wistar strain, weighing 200 g each. A solution of [14C]cefamandole, 11.8 mg/kg (23 jAmol/kg, 17.1 ,uCi), in isotonic saline solution was administered i.v. to all animals. The administered solution was prepared by dissolving 14.2 mg of [14C]nafate cefamandole (I) in 60 ul of 1.67% Na2CO3, and this solution was allowed to stand at ambient temperature for 15 min. This solution was then diluted to 600 ,lA with isotonic saline solution, pH 7.1 (23.6 mg/ml), for administration. In initial elimination studies of [14C]cefamandole 11.8 mg/kg was administered i.v. to three rats via the tail vein, and the animals were placed into individual stainless-steel metabolism cages. Urine samples were collected at 2, 4, 6, and 24 h after administration, whereas feces samples were collected after 24 h. Radiocarbon concentrations in the urine samples were determined by liquid scintillation counting. The nature ofthe radiocarbon-labeled urinary components was determined by comparison thin-layer and paper chromatography. The biologically active component was identified by comparison

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METABOLISM OF CEFAMANDOLE IN RATS AND DOGS

paper chromatography followed by bioautography, using an authentic sample of [14C]cefamandole (II). Quantitative determination of [14C]cefamandole (II) concentrations in urine samples was accomplished by microbiological assay. Feces samples were dried, ground, and analyzed for radiocarbon content by the combustion method using a Packard Tri-Carb sample oxidizer. For biliary excretion studies, three m&le rats were anesthetized with ether, and a cannula was placed into the common bile duct of each animal. After collection of a 2-h sample of normal bile fluid, [14C]cefamandole, 11.8 mg/kg, in isotonic saline was administered i.v. via the tail vein to the conscious animals, and bile fluid was collected for 24 h. Concentrations of radiocarbon were determined by liquid scintillation counting of portions (100 ,ul) of bile samples. Unaltered antibiotic was again identified by comparison chromatography using an authentic sample of [14C]cefamandole (II). Concentrations of [14C]cefamandole present in the bile were quantitated using the microbiological method described above. To determine whole-body residual radiocarbon, each animal was sacrificed 24 h after administration of [14C]cefamandole, and the carcass was dissolved in a solution of 56 g of KOH in 300 ml of ethanol heated at reflux temperature for 2 h. Three 0.5-ml samples of the resulting solution were removed, placed into small paper cups, and analyzed for radiocarbon by the combustion method. Radiocarbon blood and tissue level studies, rats. A solution of [14C]cefamandole in isotonic saline was administered i.v. to three rats via the tail vein. Whole-blood samples, 50 to 100 mg, were drawn serially from each rat via the tail vein at predetermined time intervals. The samples were processed for liquid scintillation counting using the wet-tissue digestion method of Mahin and Lofberg (4). For tissue radiocarbon distribution studies, [14C]cefamandole (11.8 mg/kg) in isotonic saline was administered i.v. via the tail vein to 12 rats. Three rats were sacrificed by decapitation at 0.5, 1, 3, and 6 h after administration. Appropriate tissues and organs were removed, and duplicate samples of each were prepared for liquid scintillation counting using the wet-tissue digestion method. Metabolism studies, dogs. [14C]cefamandole nafate (I), 208 mg, was dissolved in 0.88 ml of 1.67% Na2CO3 solution. After standing at ambient temperature for 15 min, the solution was diluted to 9.7 ml with isotonic saline (pH 7.0) solution (21.5 mg/ml). [14C]cefamandole, 10.7 mg/kg (114.5 uCi), in isotonic saline solution was given i.v. via the front leg vein to a female mongrel dog, 16 kg, fitted with a urinary catheter. Blood samples were drawn serially from the jugular vein, and urine samples were collected at specific times after administration. Two portions of each blood and urine sample were taken and processed for liquid scintillation counting. Blood samples were then centrifuged at 1,000 x g for 10 min in heparinized tubes to separate the plasma and cellular fractions. Two portions of each plasma sample were taken, and radiocarbon concentrations were determined by liquid scintillation counting.

75

The nature of the circulating and eliminated radiocarbon was determined by comparison paper chromatographic analysis. The quantitative determination of unaltered [14C]cefamandole (II) concentrations in plasma and urine was accomplished using the microbiological assay method described above. For complete elimination studies, a single 10.7mg/kg dose of [14C]cefamandole (100.2 ,tCi) was administered i.v. via the front leg vein to a bile-fistulated female mongrel dog, 14 kg, fitted with a urinary catheter. Samples of bile and urine were obtained immediately prior to, and total urinary and biliary output were collected at 30-min intervals for 6 h after, administration of the [14C]cefamandole. Duplicate samples of each bile and urine sample were taken and processed for liquid scintillation counting. The concentration of unaltered cefamandole (II) in each urine and bile sample was quantitatively determined using the microbiological assay method described above. For radiocarbon tissue level studies, an isotonic saline solution of ['4C]cefamandole, 10.7 mg/kg, was administered i.v. via the front leg vein to a female mongrel dog, 14 kg, fitted with a urinary catheter. A control sample of urine was obtained prior to administration of labeled antibiotic. Thirty minutes after administration of [14C]cefamandole, the dog was anesthetized with Seconal, and a sample of cerebral spinal fluid was drawn from the cisterna magna. After removal ofthe cerebral spinal fluid sample the dog was sacrificed, using a lethal dose of Seconal, and appropriate tissues and fluids were excised. Duplicate samples of all tissues and fluids were processed for liquid scintillation counting using the wettissue digestion method. Samples of all fluids were analyzed by microbiological assay for concentrations of unaltered [14C]cefamandole (II).

RESULTS AND DISCUSSION Rats: elimination studies. The recoveries of total radiocarbon and unaltered [i4C]_ cefamandole (II) in the urine of three rats after i.v. administration of a single dose of [14C]cefamandole are shown in Fig. 2. It is apparent from these results that renal excretion was the major route of elimination of [i4C]cefamandole (II) and/or metabolites and that this elimination was rapid. Seventy-three percent of the administered radiocarbon appeared in the urine within 2 h and 85% appeared after 24 h. Results obtained from microbiological assay of these urine samples showed that the major portion of the eliminated radiocarbon represented unaltered [14C]cefamandole (II). Total recovery of unaltered [14C]cefamandole (II) accounted for 59% of the administered dose. Thin-layer chromatographic analysis of the initial 2-h urine samples showed that 81% of urinary radiocarbon (59% of the administered dose) was eliminated as unaltered [14C]_ cefamandole (II), thus confirming the microbiological assay results. The two methods of assay,

76

SULLIVAN ET AL.

aI

a

TIAE(hrs

FIG. 2. Renal elimination of radiocarbon and of unaltered antibiotic in rats (three) after i.v. administration of 11.8 mg of [14C]cefamandole per kg.

however, failed to show the presence of detectable quantities of [14C]cefamandole nafate (I) in any urine sample. The remaining radiocarbon was associated with a number of degradation products or metabolites. The specific quantity of radioactivity associated with any one material amounted to less than 2% of the administered ['4C]cefamandole. The relative quantities of two unknown metabolites increased in relative importance to unaltered drug in later samples. Table 1 summarizes completely the results obtained in these elimination studies. Essentially all of the administered radiocarbon not eliminated by renal excretion was eliminated via biliary excretion. That fraction of the radiocarbon dose remaining in the body ofthe rats after 24 h amounted to less than 2%. These radiocarbon elimination results precluded the possibility of elimination of 14C02 as a metabolite of [14C]cefamandole. Considering the position of the radiocarbon label, the presence of radiocarbon in respired C02 would have necessitated the enzymatic cleavage of the side chain amide moiety of [14C]cefamandole and subsequent decarboxylation of the mandelic acid thus formed. Previous studies (15) have shown that mandelic acid, if formed, would have been eliminated unaltered and not decarboxylated to benzoic acid. No detectable quantity of [14C]mandelic acid was, however, found in the urine of these animals. Thus, it was apparent that enzymatic cleavage of the amide moiety of cefamandole was not inolved to any appreciable extent in its biotransformation. Elimination studies in bile-cannulated rats showed that 30.6% ofthe i.v. administered radiocarbon was elimi nated in the isolated bile

ANTIMICROB. AGENTS CHEMOTHER.

fluid (Fig. 3) in 24 h. This amount was considerably greater than that found in the feces of normal animals and implied that enterohepatic recirculation was involved in the ultimate elimination of [14C]cefamandole (II) and its metabolites in rats. The appearance of total radiocarbon and of unaltered antibiotic in bile fluid was very rapid and was essentially complete in 4 h. Microbiological and thin-layer chromatographic assay of the bile samples showed that 46% of the biliary radiocarbon represented unaltered [14C]cefamandole (II). No detectable quantity of [14C]cefamandole nafate (I) could be found in any ofthe bile samples. The remaining radiocarbon, like that in the urine, was associated with a number of degradation products or metabolites. The amount of radiocarbon associated with any one metabolite represented less than 2% of the radioactive dose. Rat blood level studies. The radiocarbon blood level curve obtained after i.v. administration of 11.8 mg of [14C]cefamandole per kg to three rats is shown in Fig. 4. This curve shows a peak concentration of 47.15-,ug equivalents of

[14C]cefamandole (II) in 10 min and then decays

in a biphasic manner. The apparent T/2 value of the initial phase, calculated using linear regression analysis, was found to be 42 min and undoubtedly represents the half-life of [14C]cefamandole (II) in the plasma after i.v. adTABLz 1. Eliminated and residual radiocarbon in three rats after i.v. administration of a single 11.8mglkg dose of[14C]cefamandole % of administered radiocarbon Radiocarbon Rat 1 Rat 2 Rat 3 Avg 84.5 91.0 80.3 85.3 ± 5.4 Urinary 14C Fecal 14C 14.1 7.2 17.9 13.1 + 5.4 Residual 14C 1.4 1.8 1.8 1.7 ± 0.3

* BILIARY RADOCARSON

*UNALTERED CEFAMANOOLE

TOWs)

FIG. 3. Biliary elimination of radiocarbon and of unaltered antibiotic in rats (three) after i.v. administration of 11.8 mg of [14C]cefamandole per kg.

VOL. 12, 1977

METABOLISM OF CEFAMANDOLE IN RATS AND DOGS

77

11.

j i

4

6

*

10

* TIME thus)

FIG. 4. Total radiocarbon blood levels in three rats after i.v. administration of11.8 mg of['4C]cefamandole

per kg.

ministration. The apparent T/2 of the second phase was calculated to be of the order of 7.2 h and can represent the half-life of a metabolite(s) of [14C]cefamandole (II) in the plasma. Rat tissue level determinations. Average radiocarbon concentrations found in various tissues, organs, and fluids of three rats 0.5, 1, 3, and 6 h after i.v. administration of a single 11.8-mg/kg dose of [14C]cefamandole are summarized in Table 2. The concentrations of radiocarbon found in these tissues are expressed as microgram equivalents of [14C]cefamandole (II) per gram of tissue. These results show that although all tissues examined contained varying concentrations of antibiotic, the only tissue possessing significantly higher concentrations than that in the blood was the kidney, the organ responsible for elimination of the antibiotic. Generally speaking, the apparent T/2 of the disappearance of radiocarbon from all tissues approximated the initial-phase T/2 of blood radiocarbon. Dogs: elimination studies. The recovery of radiocarbon and of unaltered [14C]cefamandole (II) in the urine and bile fluid of a bile-fistulated dog after i.v. administration of a single 10.7-mg/kg dose of [14C]cefamandole was very rapid and quantitative (Fig. 5). A major portion, 91%, of administered radiocarbon had been eliminated via renal excretion 2 h after

i.v. injection. Total urinary and biliary radiocarbon 6 h after administration accounted for 96 and 4%, respectively, of the administered dose. Results obtained from microbiological and thin-layer chromatographic assay of these urine and bile samples revealed that all radiocarbon present represented unaltered [14C]cefamandole (II). Neither assay procedure showed the presence of detectable quantities of [14C]cefamandole nafate (I) in any sample. It is apparent from these results that cefamandole (II) is not labile to metabolism in dogs and that it is rapidly eliminated as unaltered antibiotic primarily by renal excretion. These results are of particular interest when compared to those obtained from a recent study of the metabolic fate of a new orally effective cephalosporin antibiotic, cefaclor (11), in rats and dogs. Cefaclor is quantitatively absorbed from the gastrointestinal tract in both species. In rats this antibiotic, like cefamandole, is quite resistant to metabolism and is eliminated unchanged principally via the kidney. In dogs, however, cefaclor is more labile to metabolic degradation, and only a minor portion of the administered dose is eliminated as unaltered antibiotic. Dog blood level studies. Concentrations of radiocarbon in blood were determined in samples taken serially from a dog after i.v. administration of a single 10.7-mg/kg dose of cefa-

78

ANTIMICROB. AGENTS CHEMOTHEIR.

SULLIVAN ET AL.

TABiE 2. Total radi?carbon tissue and fluid levels in ratsa after i.v. administration of a single 11 .8-mgl kg dose of ['4C]cefamandole Radiocarbon level

Tissue

(gg equivalents of ['4C]cefamandole/ g of wet tissue) at:

6h 3h lh 0.5h 0.47 0.57 1.70 4.14 Blood 0.52 0.42 2.24 6.76 Plasma 0.44 1.31 0.42 4.96 Liver 0.12 0.08 0.13 0.53 Spleen 2.02 1.70 5.24 18.48 Kidney 0.26 0.14 0.67 2.00 Lung 0.13 0.08 1.03 0.34 Heart 0.10 0.61 0.06 5.57 Fat 0.37 0.50 3.97 0.93 Sciatic nerve 0.19 0.08 0.35 0.84 Muscle 0.13 0.07 0.39 1.71 Testicle 0.07 0.08 0.02 0.18 Brain 0.08 0.06 0.06 0.39 Eye lens a Each value represents the average value obtained from three rats. Duplicate samples of each tissue were analyzed.

i

* URNARY RADIOCARBON

a

*

BILIARY RADIOCARBON

4c

B

TUM

biotic. The plasma level curve of unaltered [14C]cefamandole (II), determined by microbiological assay of these plasma samples, is shown in Fig. 6. A comparison of this curve with the radiocarbon plasma level curve indeed confirms that the initial phase of these curves represents the disappearance of unaltered [14C]cefamandole (II) from the plasma. The T/2 value for [14C]cefamandole (II) calculated from the microbiological data was essentially the same as that calculated from the radiocarbon plasma level results for this initial 0- to 2-h to phase. Dog radiocarbon tissue level study. Radiocarbon tissue levels obtained in a dog 30 mi after i.v. injection of a single 10.7-mg/kg dose of [14C]cefamandole are summarized in Table 3. These results, like those obtained in a similar study in rats, indicated that although all tissues examined contained concentrations of the antibiotic, the only tissues possessing significantly higher levels than that found in the blood were the kidney and liver. Of the fluids examined, other than the urine and bile, only synovial fluid was found to contain significant concentrations of [U4C]cefamandole (II). This particular localization of antibiotic in the synovial fluid was also observed in a recent study of the distribution of another cephalosporin, cefaclor, in dogs (11). The quantitative recovery of unaltered ['4C]cefamandole (II) in the urine and bile of a dog after i.v. injection implies that concentrations of radiocarbon found in all tis-

("

*

RADIOCARBON LEVELS

*

UNALTERED CEfAMANDOLE

FIG. 5. Urinary and biliary elimination of radiocarbon in a female dog after i.v. administration of a single 10.7-mg/kg dose of ["4C]cefamandole.

mandole. The blood samples were separated into their plasma and cellular fractions, and then the concentrations of radiocarbon and of unaltered [14C]cefamandole (II) in each plasma sample were determined. The radiocarbon blood and plasma level curves are both bimodal in character, with the initial phase, 0 to 2 h, having a T/2 value of 30 min as calculated using the linear regression method. The second phase of each curve, 2 to 32 h, had a calculated T/2 value of approximately 50 h. In addition, these results reveal that [14C]cefamandole (II) was preferentially concentrated in the plasma fraction of the blood by a factor of 2.0 to 1. The initial phase of these curves was presumed to represent concentrations of unaltered anti-

TIW

radiocarbon and unaltered ["4C]cefamandole plasma level in a female dog after i.v. administration of a single 10.7-mglkg dose of [(4C]cefamandole. FIG. 6. Total

VOL. 12, 1977

METABOLISM OF CEFAMANDOLE IN RATS AND DOGS

TABLE 3. Total radiocarbon tissue and fluid levels in a dog 30 min after i.v. administration ofa single 10.7-mg/kg dose of[4C]cefamandole Radiocarbon level Tissue

Plasma ......................... Liver .........................

Kidney ......................... Lung ......................... Spleen ......................... Heart ......................... Ovary .........................

Adrenal ........................ Eye lens ........................ Bone marrow ................... Urine ......................... Bile ......................... Cerebrospinal fluid ........ ...... Synovial fluid .................... Aqueous humor .................

equivalents

(,ug of [14C]cefamandole/ g of wet tissue) 9.4 37.0 42.2 3.6 0.7

1.4 2.5 1.9

Metabolic fate of [14C]cefamandole, a parenteral cephalosporin antibiotic, in rats and dogs.

ANTimUcRoBiAL AGzNTs AND CHEMOTHERAPY, July 1977, p. 73-79 Copyright © 1977 American Society for Microbiology Vol. 12, No. 1 Printed in U.S.A. Metab...
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