Measurement and pharmacokinetic analysis of unbound cephaloridine in rat blood by on-line microdialysis and microbore liquid chromatography.

A technique involving rapid sampling of cephaloridine in rat blood was achieved using a combination of microdialysis and sensitive microbore liquid chromatography. A microdialysis probe was inserted into the jugular vein/right atrium of a Sprague-Dawley rat. Then after a real-time collection of the analyte by microdialysis, the dialysate was automatically injected into a liquid chromatographic system via an on-line injector. Following a 2 h stabilization period after the surgical procedure, cephaloridine (20 mg/kg, i.v.) was then administered via the femoral vein. Isocratic elution of cephaloridine was carried out with a mobile phase containing methanol-20 mM monosodium phosphate (25:75, v/v, pH 5.5), and the flow rate of the mobile phase was 0.05 mL/min within 10 min. Intra- and inter-assay accuracy and precision of the assay were each less than 10%. The in vivo recovery of the cephaloridine from the microdialysate was 49.7 +/- 8.0% and 42.4 +/- 8.4% for 0.5 and 1 microg/mL standards (n = 6), respectively. Based on the pharmacokinetic analysis, the elimination half-life was 32.2 +/- 8.6 min by cephaloridine administration (20 mg/kg, i.v., n = 6).

Effects of L-carnitine on the renal tubular transport of cephaloridine.

It has been demonstrated recently that cephaloridine (Cld) inhibits the tubular reabsorption of filtered carnitine (Carn) in the rabbit kidney. This interaction has suggested that the limited net cell-to-luminal fluid movement of Cld following its secretory transport across the antiluminal membrane might result from a balance of active Cld reabsorption by a Carn carrier at the brush border approximately equal to its secretion into the tubular fluid, rather than the previously proposed luminal membrane block. Studies were done to determine the effects of L-Carn, 750 mg/kg, i.v. on the tubular secretion and cortical concentrations of Cld, infused i.v. at a dose of 28 mg/kg (Carn:Cld molar ratio = 70:1). The fractional excretions of Cld during three consecutive periods of 10 min each, one before and two following the bolus infusion of Carn, were (means +/- SEM): 1.18 +/- 0.14, 1.20 +/- 0.14, and 1.16 +/- 0.11, respectively (N = 6 each; differences NS). Cortex-to-serum concentration ratios of Cld in control and Carn-treated rabbits were 10.43 +/- 0.32 and 10.16 +/- 0.86, respectively (NS). The data provide evidence against the reabsorptive transport of Cld by a Carn carrier, and do not support a model of balanced secretion and reabsorption as the cause of limited clearance despite significant secretory transport of Cld into the tubular cell.

Influence of endogenous and exogenous Jaffé-reaction-positive pseudo-creatinine chromogens in determination of creatinine in blood of normal and cephaloridine-administered rats.

To investigate a magnitude of analytic errors brought by certain interfering substances to the chemical method using Jaffé-reaction for determination of creatinine, two sorts of values determined by the chemical method and by the HPLC method were compared between each other, in blood samples obtained from control and cephaloridine (CER)-administered rats. The rats that received an intravenous injection of CER in dose of 1,000 mg/kg body weight, showed two peaks at the 1-hour and on the 3-day. Since the color development of CER determined in the chemical method showed that 1 g of CER corresponded to 0.0208 g of creatinine, the results of plasma CER determination proved that the first peak was ascribable to the color development of CER. As to the second peak, no significant difference was observed between the values of the two methods. This finding denoted that, when the creatinine levels were elevated, the two sorts of values due to the two methods approached to one another, and suggested that the ratio of "endogenous Jaffé-reaction-positive pseudo-creatinine chromogens" to "total Jaffé-reaction-positive chromogens" would be decreased according as the "true" creatinine was increased. In the control rats, the ratio to "total Jaffé-reaction-positive chromogens" was 60% in terms of "true" creatinine, and 40% in terms of "endogenous Jaffé-reaction-positive pseudo-creatinine chromogens."

Protective effect of piperacillin against nephrotoxicity of cephaloridine and gentamicin in animals.

The protective effect of piperacillin against the nephrotoxicity of cephaloridine and gentamicin was examined in experimental animals. In rabbits, piperacillin was infused at a dose of 1 mg/kg (body weight) per min over 225 min and cephaloridine (300 mg/kg) was intravenously administered as a bolus 45 min after the start of a drip infusion. Blood urea nitrogen, serum creatinine, and N-acetyl-beta-D-glucosaminidase (NAG) in urine were measured as the renal toxicological parameters before and 24 h after cephaloridine dosing. Although the single administration of cephaloridine significantly elevated these parameters, the elevation was prevented by the concomitant administration of piperacillin. The protective effect of piperacillin was superior to those of cephalothin and fosfomycin. In rats, piperacillin (1,000 mg/kg) was intravenously administered and immediately followed by the intramuscular administration of gentamicin (100 mg/kg) every 24 h for 5 days. When piperacillin was concomitantly administered with gentamicin, the elevations of blood urea nitrogen, serum creatinine, and urinary NAG were significantly lower than when gentamicin was given alone. The concomitant administration of piperacillin resulted in a significant protective effect against the nephrotoxicity of cephaloridine in rabbits and of gentamicin in rats. Histopathological observation also supported the protective effect of piperacillin. The protective mechanism of piperacillin might be the inhibition of transport from the peritubular side to tubular cells for cephaloridine and from both the peritubular and luminal sides for gentamicin.

The utility of diffusion chambers as models for the description of drug disposition.

Tissue cages were employed to explore the diffusion processes of several cephalosporins into extravascular fluids. Concentrations of cefotaxime in serum and in subcutaneous chambers increased proportionally to the amount of the drug injected. Administration of single equal doses of cephalothin, cephaloridine and cefotaxime resulted in different concentration-time courses in the serum and in diffusion chambers. These observations suggest that diffusion chambers are linked to the tissue at the implantation site. None of the classical compartmental approaches can be applied to evaluate the kinetics of drug diffusion into tissue cages. Correlations of total or non-protein bound drug concentrations in tissue cages to those in the peripheral compartment assumed concentration and time dependent diffusion processes. No specific diffusion constant based on the law of Fick could be derived for the diffusion chambers used in this study. Concentration-time courses in serum and interstitial fluid can be simultaneously evaluated according to pharmacokinetic-pharmacodynamic models. Based on the equation describing the effect site this model can be used to simulate drug concentrations in tissue cages by varying the dose size or the dose interval.

Covalent binding of cefotaxime to human serum albumin.

The covalent binding ratio of cephalosporins (CEZ, CER, CET and CTX) to human serum albumin was examined at pH 7 and pH 10. The antibiotic equivalents were larger at pH 10 than at pH 7. The degree in the binding ratio of the 4 cephalosporins was CET greater than CER greater than CTX greater than CEZ at pH 7 and CER greater than CET greater than CTX greater than CEZ at pH 10.

[Pharmacokinetics of cephaloridine (author's transl)].

I studied on absorption and excretion of cephaloridine. Cephaloridine was administered intravenously to 5 healthy volunteers weighing 65 kg to 83 kg, and the blood levels were measured. A cross over test subjecting 2 grams intravenous drip infused for 1 hour against the same dose for 2 hours were performed after 1 week interval. The disposition of cephaloridine was estimated by applying one-compartment model which was scaled from YOKOKAWA & HULET PACKARD'S disc top computer. Pharmacokinetic parameters are as followings: 1 hour d.i.v.: Kel 1.410 (hr-1), Vd 9.629(L), T 1/2 30.290 (min.) 2 hours d.i.v.: Kel 0.876 (hr-1), Vd 21.106(L), T 1/2 49.372 (min.).

Importance of beta-lactamase inactivation in treatment of experimental endocarditis caused by Staphylococcus aureus.

To test the hypothesis that cephalosporins resistant to beta-lactamase are preferred in the treatment of serious staphyloccal infections, the ability of four cephalosporins to eradicate bacteria from the cardiac vegetations of rabbits with experimental endocarditis was examined. Two strains of Staphylococcus aureus were chosen as pathogens: one that rapidly and completely inactivated 50 micrograms of cefazolin in vitro (beta-lactamase-positive) and another that did not inactivate any cephalosporin (beta-lactamase-negative). Rabbits with a polyethylene catheter in the left ventricle were reliably infected witih 10(5) bacteria. Similar numbers of S. aureus were recovered from the cardiac vegetations of rabbits inoculated with the beta-lactamase-positive strain after 24 hr of treatment with each of four cephalosporins. However, when the animals were treated at intervals of 6 hr for four days, significantly fewer rabbits survived after treatment with cefazolin than with cephalothin. No difference in survival was observed in the treatment of rabbits with endocarditis due to the beta-lactamase-negative strain. The failure of cefazolin in the treatment of staphylococcal endocarditis in rabbits may be due to inactivation of the drug by beta-lactamase in vivo.

Renal excretion of cephapirin and cephaloridine: evidence for saturable tubular reabsorption.

Drug concentrations in plasma and urine were determined in 5 healthy subjects after intravenous infusion of 1 gm cephapirin and cephaloridine. Sampling of blood and urine was frequent and prolonged. Specimens were analyzed by high-pressure liquid chromatography (HPLC). Renal clearance of cephapirin decreased to less than 5% of control in all subjects when drug concentrations in plasma and urine declined. Cephaloridine clearance decreased to a lesser extent. Our findings suggest that, besides tubular secretion and glomerular filtration, a saturable and probably active tubular reabsorption is also involved in the renal handling of these two cephalosporins. The saturable reabsorption process was characterized by its Michaelis-Menten constant Km and its maximum transport capacity Tm.

Intra-incisional cephaloridine: a comparison of two methods of administration.

Serum cephaloridine concentrations were measured in the immediate post-operative period in 23 patients who had received a prophylactic dose of 1 g of the drug into the wound at the end of operation. Eleven patients received the antibiotic as a powder and 12 as a solution. The serum concentrations were higher, though not significantly so, in the group receiving powder, and this is thought to be due to the lesser amount of spillage and loss into dressings when the antibiotic is given in this form.

[Experimental studies on the passage of antibiotics into cerebrospinal fluid in staphylococcal meningitis in rabbits. II. Cephaloridine, cephalothin and cefazolin (author's transl)].

Passage of cephaloridine, cephalothin and cefazolin into cerebrospinal fluid (CSF) was evaluated in Staphylococcus aureus meningitis in rabbits and the following results were obtained. 1. Concentration in CSF (microgram/ml) [CSF/serum ratio (%)] was determined 1/2, 1 and 2 hours after a single intravenous injection of 100 mg/kg of each antibiotic, respectively; cephaloridine-7.5 [8.9], 9.7 [13.8], 9.1 [22.6]; cephalothin-0.42 [3.6], 0.23 [6.4], not detectable [0]; cefazolin-7.5 [11.8], 5.2 [19.3], 2.0 [17.5]. 2. When results with cefazolin after an intravenous injection 100 mg/kg and 200 mg/kg were compared, a definite dose response was noted in blood concentration but not in CSF concentration. 3. A standard error of CSF concentrations of each antibiotic was larger than that of penicillins, and "Unpredictability" of their passage into CSF was considered to be one of the characteristics common to these three drugs in respect of their passage into CSF. 4. There was no significant difference noted in antibiotic passage into CSF between cephaloridine of low protein binding rate and cefazolin of very high binding rate. Cephalothin, of which binding rate was intermediate, showed a remarkably lower passage into CSF. These results indicate that a correlation does not always exist between protein binding rate of the antibiotics and their passage into CSF. 5. Based on the above results, a review of the literature was made on clinical applicability of these three antibiotics in the treatment of bacterial meningitis. Low transport rate of cephalothin into CSF and nephrotoxicity of cephaloridine make them to be unsuitable for bacterial meningitis. Cefazolin is considered to be suitable in the treatment of ampicillin-resistant Escherichia coli meningitis and Gram-positive coccal meningitis in which penicillins are not applicable.

Age-dependent renal accumulation of cephaloridine in the rabbit.

The accumulation of cephaloridine in the renal cortex of the rabbit was studied in vitro and in vivo in rabbits of various ages. The cortical concentration of cephaloridine, the cortex/serum ratio, and the slice/medium ratio determined by incubation of cortical slices in cephaloridine-containing media rose from birth to adult levels at approximately 1 month of age. Pretreatment with procaine penicillin G stimulated the ability to accumulate cephaloridine in vitro and in vivo. The data indicate that the lack of susceptibility of immature rabbits to cephaloridine nephrotoxicity is due to the lack of development of the anionic transport system which is apparently necessary to achieve the high cortical concentrations of cephaloridine that result in renal injury.

[Antibiotic concentration in postoperative wound fluid during short-term prevention with cephalosporins]. / Antibiotikakonzentrationen im postoperativen Wundsekret bei Kurzprophylaxe mit Cephalosporinen.

Antibiotic concentrations were measured in wound fluid from Redon-drains and in serum during short-time prophylaxis in orthopaedic surgery. 1. Chephaloridine and cephazolin concentrations in wound fluid rose to therapeutic levels. 3 h after i.v. application of 1 g concentrations in wound fluid and in serum were nearly identical. 6 and 12 h after application the concentrations in wound fluid were significantly higher than those in the serum. 2. At the end of the 12-h interval of administration the mean concentrations of both antibiotics as well in wound fluid as in serum remained at therapeutic levels. 3. For reasons of their good diffusion into the wounds both cephaloridine and cefazolin should be appropriate for short-time prophylaxis in orthopaedic surgery.

Effects of furosemide on glomerular filtration rate and clearance of practolol, digoxin, cephaloridine, and gentamicin.

Furosemide was shown to decrease inulin clearance in 20 of 27 normal subjects. The depression in inulin clearance occurred in both water-loaded and non-water-loaded subjects. The renal clearance of practolol, but not digoxin, was reduced when furosemide was given. The average total plasma clearances of gentamicin and of cephaloridine over a 6-hr period were decreased after furosemide. The reduced clearances of the antibiotics were associated with higher plasma levels, the increase in antibiotic concentration being as much as 100% at 1 hr after an intravenous bolus injection.

Half-life of cephaloridine in dogs with reduced renal function.

Various degrees of renal insufficiency were produced in 9 dogs by nephrectomy, or segmental ligation of the branches of the renal artery, or both. The serum half-life of cephaloridine, measured after a single intramuscular injection, increased progressively as renal function decreased. In dogs with 85% reduction in renal mass, serum half-life was approximately 3 times that of control dogs. To prevent accumulation of cephaloridine in dogs with renal dysfunction, a modified dose schedule was established on the basis of these experimental results.