Levels of Carbenicillin, Ticarcillin, Cephalothin, Cefazolin, Cefamandole, Gentamicin, Tobramycin, and Amikacin in Human Serum and Interstitial Fluid

The effect of protein binding on drug penetration into blister fluid was evaluated by using cefonicid, ceftizoxime, and cefotaxime. Drug concentrations in a chamber with a high surface area/volume ratio (i.e., paper disk) follow changes in serum more closely than do those in a chamber with a low surface area/volume ratio. Both the area under the concentration-time cu'rve ratio and the concentration ratio (by the disk method) for cefonicid were statistically lower than the ratios for ceftizoxime and cefotaxime. The high degree of protein binding of cefonicid results in the availability of less drug for diffusion to blister fluid than with the low-protein-binding ceftizoxime and cefotaxime.Drug concentrations in blister fluid are critical, since most bacterial infections occur in the interstitial space and not the intravascular space. Many investigators have tried to correlate the penetration of P-lactam antibiotics into interstitial fluid with the degree to which the drugs bind protein.However, such studies have yielded disparate results, as shown by reports of poor cefazolin extravascular penetration in one study (11,12) and of good penetration in other studies (1,4,5,7,8).Cefonicid is 98% bound to serum protein and is used for the treatment of skin and soft tissue infections (3). In view of the high degree of protein binding of this compound, the penetration of the drug into blister fluid was compared with the penetrations of ceftizoxime and cefotaxime (<40% bound) by using a modified suction blister technique (10).Six healthy volunteers (four male and two female) between the ages of 25 and 29 years and weighing 51 to 80 kg were enrolled in this study. Female volunteers were not pregnant or receiving oral contraceptives.Each subject received a single 30-mg/kg (body weight) dose of cefonicid, ceftizoxime, or cefotaxime on three occasions. A treatment schedule was assigned randomly to each subject. There was at least 1 week between doses. Drugs were given by constant intravenous infusion over 5 min into an antecubital vein via an indwelling intravenous catheter. Nornmal saline (3 ml) was injected immediately after the infusion to flush the catheter. Blood samples were obtained from the cannulus, after discarding the first 2 ml, at 0,5,10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 480, 600, 720, and 1,440 min after dosing. Each volunteer had eight skiii blisters produced on his or her forearm by the modified suction blister technique previously described by Shyu et al. (10).In the protein-binding study, cefonicid standards were prepared in freshly pooled human serum at 37°C at 450, 400, 350, 300, 250, 175, 150; 125, 100, 75, 50, 25, and 12.5 immediately after preparation. Ultrafiltration was performed at 37°C and 1,000 x g for 15 min.Cefonicid concentrations were determined by a microbiological assay with Bacillus subtilis ATCC 6633 as the test organism. Serum standards were prepared in pooled serum, and blister fluid standards were prepared in 50% pooled serum and 50% phosphate buffer (0.1 M, p...

mentioning

confidence: 94%

Effect of protein binding on drug penetration into blister fluid

Shyu

Quintiliani

Nightingale

et al. 1988

“…The combination of high serum levels and a reduced rate of excretion provides a prolonged half-life with sustained serum levels, which are thought to be responsible for superior tissue penetration (4,5,16,24). Although the ability of cefazolin to enter osseous tissue has been evaluated with bioassay techniques (6,11,23,31,32,35), the information obtained fails to fully define the osseous pharmacokinetics. Additionally, the osseous levels determined by bioassay have an erratic relationship to simultaneously determined serum levels (6,23,26,29).…”

mentioning

confidence: 99%

Penetration of cefazolin into normal and osteomyelitic canine cortical bone

Daly¹,

Fitzgerald²,

Washington³

1982

The ability of cefazolin to cross the capillary membranes and its concentrations in the interstitial fluid spaces were studied in normal and osteomyelitic canine bone. The maximum extraction after a single capillary passage and the net extraction after 3 min, determined with triple-tracer indicator-dilution techniques, demonstrated that cefazolin readily traversed the capillaries of normal and osteomyelitic bone. These studies suggest that the altered pathophysiology of osteomyelitic tissue and the complex diffusional characteristics of cefazolin enhanced the ability of this agent to cross the endothelial cells lining the capillaries of osteomyelitic bone. Volume of distribution studies demonstrated that cefazolin was distributed in the plasma and interstitial fluid spaces of normal cortical bone.Although these spaces were increased 330 and 941% in osteomyelitic tissue, the distribution of cefazolin increased proportionally. There was a direct correlation between the calculated concentrations of cefazolin in the interstitial fluid spaces of normal and osteomyelitic cortical bone and the simultaneous serum levels in animals in which a steady-state equilibrium had been achieved. These studies suggest that a physiological barrier or concentration gradient for cefazolin does not exist in normal or osteomyelitic bone. Cefazolin can cross the capillary membranes of bone and achieve bactericidal concentrations in the interstitial fluid space of normal and osteomyelitic tissue.

“…Carbenicillin (CBPC) has been used clinically since the late 1960s, and its pharmacokinetics have been extensively studied both in humans (8,12,13,17,19,20) and in animals (1,9,16,21). However, it has been used as a mixture of two epimers (R-CBPC and S-CBPC) because of the chirality of a (carboxyphenylacetyl)amino group attached to the 6 position of a penicillanic acid.…”

mentioning

confidence: 99%

Stereoselective renal tubular secretion of carbenicillin

Itoh

Ishida

Onuki

et al. 1993

The stereoselective disposition of carbenicillin epimers was studied in healthy human volunteers. There was a difference between the two epimers in the extent of plasma protein binding in vitro, with the unbound fraction of the R epimer being greater than that of the S epimer. Renal clearance (CLR) of each epimer was greater than the glomerular filtration rate, suggesting renal tubular secretion of both epimers. Although the CLR was greater for the R epimer, renal tubular secretion was greater for the S epimer. When probenecid was coadministered, the CLR of each epimer was significantly reduced and was approximately equal to the glomerular filtration rate. The difference in CLR between the two epimers was simply due to differences in plasma protein binding. The observations in the present study suggest that both carbenicillin epimers are secreted by an organic anion transport system in the renal proximal tubule in humans and that the two epimers may be distinguished in the secretion process, resulting in the differences in the secretion rates.