Protein Binding of Ceftriaxone in Extravascular Fluids

The relevance of protein binding to penetration of ␤-lactams into body fluids was investigated by examining the distribution of amoxicillin, ceftriaxone, clavulanic acid, temocillin, and ticarcillin into rabbit peripheral lymph after intravenous administration. The elimination half-lives in rabbit plasma varied between 0.34 h (temocillin) and 1.80 h (ceftriaxone), and the half-lives measured in lymph were similar to those in plasma (0.37 to 1.76 h). The percent penetration (area under the concentration-time curve in lymph/area under the concentration-time curve in plasma ؋100) was high for amoxicillin (97.6%), temocillin (89.4%), and clavulanic acid (90.8%) but was lower for ticarcillin (76.0%) and for ceftriaxone (67.3%). There was a direct correlation between plasma protein binding and percent penetration. Correction for plasma and tissue binding increased the percent penetration for all compounds, and figures approached 100%. The results presented demonstrate the use of this model to examine the relationships between plasma pharmacokinetics, protein binding, and distribution of antibiotics.The extent of extravascular penetration of ␤-lactam antibacterial agents is an important contributing factor to their clinical efficacy. The physiochemical characteristics of the compound, for example, molecular weight, lipid solubility, and pK a , control their rate and extent of diffusion across membranes and throughout body tissues and fluids. Binding to serum and tissue proteins influences this penetration, in addition to influencing body clearance and the extent to which concentrations are effective at the site of infection, as it is only the free antibiotic which is available for diffusion and antibacterial activity (5, 18).The effects of serum binding on the distribution of antibiotics have been examined extensively (1,3,11,15,23), but there remains some discussion as to whether binding to serum proteins below 85% is of major importance with respect to the rate and extent of penetration and body clearance (2, 6). The contribution of tissue binding in other body tissues and fluids to the overall distribution of agents is generally less well documented, although the extent of distribution in terms of total concentrations (bound plus free) is presumed to be dependent upon both the serum and the tissue binding (5, 7, 13).The extravascular concentration-time profiles are influenced by other factors such as the ratio of surface area for diffusion to volume of extravascular fluid. This has been demonstrated both theoretically (17) and practically (22). The elimination half-life in serum influences the duration of extravascular concentrations, and compounds with longer elimination half-lives achieve more sustained extravascular levels. In addition, the mode of administration will directly affect the concentrations observed.None of these factors can, however, be considered in isolation, and in this paper, the interrelationship of protein binding with concentrations in extravascular tissues has been considered for amoxicillin,...

Section: Resultssupporting

confidence: 77%

Effect of protein binding on penetration of beta-lactams into rabbit peripheral lymph

Woodnutt

Berry

Mizen

1995

“…With respect to the free fraction of CTX, Table 2 enables comparison of our results with those obtained by Stoeckel et al (26) after administration of a dose of 1,500 mg to six healthy volunteers; values of the various parameters were very similar. The kinetics of total CTX are nonlinear, while those of the free fraction are linear because of concentration-dependent protein binding (17,22,26).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and protein binding of ceftriaxone during pregnancy

Bourget

Fernandez

Quinquis

et al. 1993

The purpose of the present work was to study the pharmacokinetics and the protein binding (free fraction of the drug) of ceftriaxone (CTX) during pregnancy. Nine pregnant women (ages, 20 to 34 years) whose gestational ages ranged from 28 4/7 to 40 5/7 weeks were included. The diagnosis of infection was established in all cases; i.e., four women had chorioamnionitis and five women had pyelonephritis. The following triple antibiotic therapy was infused with the aim of achieving cure: CTX, 2 g once every 24 h (constant rate over 60 min); tobramycin, 3 mg/kg of body weight once every 24 h; and ornidazole, 1 g/day. Two series of blood samples were collected, i.e., during the first day of treatment (on day 1), to establish the primary pharmacokinetic profile of CTX, and at the plateau (on day 7), to evaluate a possible accumulation of the drug.This was an open, noncompartmental study, with each patient serving as her own control. Concentrations of total and unbound CTX in serum were measured by a high-performance liquid chromatographic method. Pharmacokinetic analysis was done by a noncompartmental method. Data were compared by a Wilcoxon t test (a P value of .0.05 was considered significant). Data were also compared with those obtained for healthy subjects who received similar treatments. (i) The tolerance to treatment was excellent, and in all cases patients had a complete remission without premature delivery. (ii) No accumulation of CTX was noted during the treatment, and the profiles of the drug determined at days 1 and 7 were not significantly different. (iii) The pharmacokinetic parameters measured in pregnant patients during the third trimester of pregnancy were similar to those measured in healthy subjects. (iv) Residual concentrations of total and unbound CTX measured at 24 h were greater than the MICs for allegedly susceptible organisms, both on day 1 and at steady state. (v) During the final 3 months of pregnancy, the dosage schedule of CTX (2-g infusion per day) required no particular adjustment (i.e., neither a loading dose nor any increase in the maintenance dose).Ceftriaxone (CTX) is the first broad-spectrum cephalosporin prescribed on a single-daily-administration basis (24). This dosage schedule, which is unusual for a beta-lactam antibiotic, has been validated by a number of clinical studies since CTX came onto the market (11, 31). A pharmacodynamic and bacteriological approach taken together with the specific pharmacokinetics of the compound have formed the theoretical basis of a simplified administration schedule compared with those for other beta-lactams with shorter half-lives (9). The dosage recommended by the manufacturer (a single injection of 1 to 2 g every 24 h) is the consequence of an essential peculiarity of CTX: its prolonged terminal half-life (between 6.5 and 8.5 h) (21). The antibacterial spectrum of CTX is similar to that of other broad-spectrum cephalosporins. However, in comparison with other members of the group, it is less active against anaerobic organisms such as Bacteroides fr...

“…We found that high concentrations of methylprednisolone hemisuccinate (150 ,ug/ml, approximating peak concentrations found in the surgery patients) in a human serum albumin solution (1.5 g/dl) reduced ceftriaxone binding from the control level (78.2% bound) to 70.3% bound. Binding in normal serum or human serum albumin (4 g/dl) with similar ceftriaxone concentrations is between 93 and 96% (22), illustrating the effect of low albumin concentrations. In vitro addition of 1.5 and 3 mM FFA (30% palmitic, 10% stearic, 20% linoleic, and 40% oleic acids) to plasma samples from normal volunteers, plasma diluted to 37.5% (to give about 1.5 g of albumin per dl), and 1.5 g/dl of human serum albumin also decreased ceftriaxone binding.…”

Section: Discussionmentioning

confidence: 99%

“…Second, after surgery, acute-phase reactive protein synthesis increases, possibly at the expense of albumin synthesis (1). Ceftriaxone binds to one site on albumin with a relatively low affinity constant (Ka 104 liters/mol) (22). Theoretically, the concentration of binding protein would have a proportional effect on binding for drugs with low affinity, like ceftriaxone (13).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ceftriaxone disposition in open-heart surgery patients

Jungbluth

Pasko

Beam

et al. 1989

The effects of cardiopulmonary bypass (CPB) with hypothermia and systemic heparinization on ceftriaxone disposition were evaluated in seven male patients. A bolus dose of drug (14 mg/kg of body weight) was given, and blood and urine specimens were collected before, during, and after CPB for 96 h. Creatinine, albumin, and total and free ceftriaxone concentrations in plasma were measured. The ceftriaxone free fraction (ff) in vitro was estimated by equilibrium dialysis, and the in vivo ff was obtained by the ratio of renal clearance due to filtration to creatinine clearance. Pharmacokinetic parameters were based on concentrations of total drug and free drug. Albumin decreased from 3.10 ± 0.29 g/dl presurgery to 1.42 ± 0.17 g/dl and recovered to 2.46 ± 0.26 g/dl on postoperative day 4. CPB markedly increased the in vitro ff, which was reversed by protamine post-CPB (if pre-CPB, 0.15 ± 0.01; during CPB, 0.53 ± 0.20; post-CPB, 0.16 ± 0.02). The in vitro ff exceeded the in vivo if (0.53 ± 0.20 versus 0.24 ± 0.07), probably due to continued free fatty acid release caused by heparin during dialysis. Clearances based on free drug decreased, and the renal clearance due to filtration increased (7.6 ± 2.8 versus 15.0 ± 4.5 ml/min) while the creatinine clearance decreased (114 ± 29 versus 72 + 28 ml/min) during CPB. Diminished binding owing to low albumin and free fatty acids explain this behavior.Lower binding also increased the volume of distribution (154 ± 41 ml/kg) and extended the half-life (15 ± 6 h). In summary, ceftriaxone disposition was significantly altered by CPB, resulting in marked increases in free drug concentrations, half-life, and volume of distribution and in decreased intrinsic clearance.