Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics

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Abstract
The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose‐dependent increase in total systemic clearance (ClTS) from 9.7 ml/min at the 150‐mg dose to 13 ml/min at the 1500‐mg dose. The dose‐dependent changes in ClTS could be explained in terms of the concentration‐dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCF0–∞) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (CIFR) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (CIFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t½ was not influenced by dose and averaged 8 hr. This biologic t½ is by far the longest ever for a cephalosporin in healthy subjects. Clinical Pharmacology and Therapeutics (1981) 29, 650–657; doi:10.1038/clpt.1981.90