Plasma protein binding of ceftriaxone.

1. The plasma protein binding characteristics of ceftriaxone, a new cephalosporin antibiotic, were determined in human, baboon, rabbit, dog and rat plasma. 2. The protein binding of ceftriaxone was similar and concentration-dependent in human, baboon, rabbit and rat plasma, being highly bound (90-95%) at low concentrations (less than 100 micrograms/ml) but considerably less bound (approx. 60%) at high concentrations (greater than 400 micrograms/ml). Binding in dog plasma was also concentration-dependent but much lower (approx. 25%) at lower concentrations (30 micrograms/ml) and virtually unbound (2%) at high concentrations (1 mg/ml) over a similar concentration range. 3. Binding of ceftriaxone to human plasma involved two sites: a high affinity-low capacity (saturable) site and a low affinity-high capacity site. Binding to dog plasma apparently was at a single, high affinity-low capacity site. 4. The pharmacokinetics of ceftriaxone in an animal species with binding characteristics similar to man (baboon), appear to be non-linear when based on total drug concentration and linear when based on the free drug concentration. In the dog, pharmacokinetic parameters did not change appreciably if calculated from total or free drug concentrations, due to the low protein binding.

Disposition of bumetanide in the isolated perfused rat kidney: effects of probenecid and dose response.

The isolated perfused rat kidney was used to study the pharmacokinetic-pharmacodynamic relation of bumetanide and furosemide. Diuresis, as indicated by the concomitant increase in urine volume and fractional excretion of sodium, was produced with both drugs. The action of furosemide was dependent on a high clearance resulting from combined glomerular filtration and tubular secretion. The site of furosemide action was the luminal side of the nephron and a large amount of drug was required in the tubular lumen to produce diuresis. A bidirectional transport of bumetanide was indicated. Although tubular secretion of bumetanide was demonstrated, the action of bumetanide was not dependent on secretion and the highest response was achieved when bumetanide was filtered and partially reabsorbed. The lack of dependency on secretion to produce a response may be indicative of bumetanide reaching its site of action from the luminal as well as the vascular side of the nephron. In the isolated perfused rat kidney, although both drugs had the same pharmacodynamic endpoint, each drug had a different pharmacokinetic profile that characterized its response.

Influence of protein binding and metabolic interconversion on the disposition of sulfisoxazole and its N4-acetyl metabolite by the isolated perfused rat kidney.

The renal clearances of sulfisoxazole (SX) and N4-acetylsulfisoxazole (NSX) were studied in the isolated perfused rat kidney (IPK). Studies were conducted with conventional bovine serum albumin perfusates as well as with dextran perfusates to assess the influence of perfusate protein binding on the disposition of these compounds by the IPK. The results presented herein indicate that the disposition of sulfisoxazole by the IPK involves both metabolism and excretion. The metabolism of SX to NSX is reversible and is influenced by protein binding since metabolism increased with increased free fraction (Ff). The excretion of SX and NSX reflects a complex interaction of filtration, secretion, and reabsorption. A comparison of clearance values between kidneys perfused with bovine serum albumin perfusate (Ff 0.1) and dextran perfusate (Ff 1.0) suggests that tubular secretion of SX is a function of total (unbound plus bound) rather than free (unbound) drug in the perfusate.

Gentamicin-specific antiserum alters the disposition of gentamicin by the isolated perfused rat kidney.

Previous studies have indicated that antibodies or Fab fragments of antibodies can be used to alter the pharmacologic or toxicologic effects of drugs. The present study was conducted to determine the effect of specific antiserum administration on the renal excretion of a drug with a high nephrotoxic potential (e.g., gentamicin) using the IPK. After a perfusion period during which the renal clearance of gentamicin was determined, either serum or gentamicin-specific antiserum was added to the perfusion medium. Experiments with serum addition served as controls for a comparison of the effects of antiserum addition on gentamicin renal clearance and tissue accumulation. Addition of antiserum decreased the renal clearance and tissue accumulation of gentamicin. Increasing perfusate gentamicin concentrations at the end of the experimental time suggested that these alterations in disposition could be due to the formation of a nonfilterable gentamicin-antiserum complex. The addition of antiserum also rapidly reversed the increasing fractional excretion of potassium ion. Therefore it would appear that a commercially available antiserum is capable of decreasing renal tissue accumulation of gentamicin and that the IPK represents a viable system for studying the effects of antisera on renal drug disposition.